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Chemical-Induced Coordinated and Reciprocal Changes in Heme Metabolism, Cytochrome P450 Synthesis and Others in the Liver of Humans and Rodents

Chemical-Induced Coordinated and Reciprocal Changes in Heme Metabolism, Cytochrome P450 Synthesis and Others in the Liver of Humans and Rodents

The Journal of Toxicological Sciences (J. Toxicol. Sci.) SP89 Vol.41, Special Issue, SP89-SP103, 2016

Review Chemical-induced coordinated and reciprocal changes in , P450 synthesis and others in the liver of humans and rodents

Takemi Yoshida1, Takashi Ashino2 and Yasuna Kobayashi3

1Council on Pharmacists Credentials, 7F Yusei-Fukushi Tranomon Dai-ichi Bldg., 2-9-14 Toranomon, Minato-ku, Tokyo 105-0001, Japan 2Division of Toxicology, Department of Pharmacology, Toxicology and Therapeutics, Showa University School of Pharmacy, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan 3Department of Pharmacology and Therapeutics, Niigata University of Pharmacy and Applied Life Sciences, 265-1 Higashijima, Akiha-ku, Niigata city, Niigata 956-8603, Japan

(Received December 31, 2016)

ABSTRACT — A wide variety of drugs and chemicals have been shown to produce induction and inhi- bition of heme-metabolizing , and of drug-metabolizing enzymes, including cytochrome P450s (P450s, CYPs), which consist of many molecular species with lower substrate specificity. Such chemi- cally induced alterations are coordinately or reciprocally regulated through the same and/or dif- ferent signal transductions. From the toxicological point of view, these enzymatic changes sometimes exacerbate inherited diseases, such as precipitation of porphyrogenic attacks, although the induction of these enzymes is dependent on the animal species in response to the differences in the stimuli of the liver, where they are also metabolized by P450s. Since P450s are , their induction and/or inhibition by chemical compounds could be coordinately accompanied by heme synthesis and/or inhibi- tion. This review will take a retrospective view of research works carried out in our department and cur- rent findings on chemical-induced changes in hepatic heme metabolism in many places, together with current knowledge. Specifically, current beneficial aspects of induction of heme -1, a rate-lim- iting heme degradation enzyme, and its relation to reciprocal and coordinated changes in P450s, with special reference to CYP2A5, in the liver are discussed. Mechanistic studies are also summarized in rela- tion to current understanding on these aspects. Emphasis is also paid to an example of a single chemical compound that could cause various changes by mediating multiple signal transduction systems. Current toxicological studies have been developing by utilizing a sophisticated “omics” technology and survey integrated changes in the tissues produced by the administration of a chemical, even in time- and dose-de- pendent manners. Toxicological studies are generally carried out step by step to determine and elucidate mechanisms produced by drugs and chemicals. Such approaches are correct; however, current “omics” technology can clarify overall changes occurring in the cells and tissues after treating animals with drugs and chemicals, integrate them and discuss the results. In the present review, we will discuss chemical-in- duced similar changes of heme synthesis and degradation, and of P450s and finally convergence to simi- lar or different directions.

Key words: Chemical compounds, Heme metabolism, Cytochrome P450s, δ-Aminolevulinic acid synthase, , Transcritional factors

INTRODUCTION of hemoproteins. Heme also functions as gas transport- ers, electron transmitters, and numerous enzymes or pro- Heme is a chelate substance of protoporphyrin IX and teins, and thus is an indispensable molecule in the body ferrous (Fe2+), and it serves as the prosthetic group (Ponka, 1999). Cellular heme levels are precisely tuned

Correspondence: Takemi Yoshida (E-mail: [email protected])

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T. Yoshida et al. by heme biosynthesis and catabolism, by controlling 2008). Furthermore, HO-1 and its enzymatic products at δ-aminolevulinic acid (ALA) synthase (ALAS), and play various physiological roles in the body. Thus, HO-1 heme oxygenase (HO) either by induction and/or inhibi- induction and its reaction products are now recognized tion mechanism so as to maintain a free and bound heme to have important defensive and regulatory roles for pro- pool. tecting cells and tissues from noxious chemical stimuli or The liver is known to be one of the important heme- oxidative stresses such as pathophysiological conditions, synthesizing tissues, of which over 50% of biosynthe- including vascular protective, arterio-protective, and anti- sized heme is utilized for (CYP or inflammatory roles. Since the protective effects of HO-1 P450) synthesis. P450s are important enzymes which induction on pathophysiological conditions, except for the catalyze oxidative metabolism of endogenous substanc- liver, are out of scope in this review, please refer to recent es and exogenous chemical compounds. P450s consist excellent reviews by Faronbi and Surh, (2006), Paine et of many molecular species and many of them are induc- al. (2010), Sass et al. (2012), and Zhou et al. (2015). ible in a species-specific manner in response to various Ryter and Choi (2016) have recently reviewed and dis- endogenous and exogenous stimuli. However, ethnic and cussed HO-1 and its reaction products such as carbon individual differences in P450s in humans are important monoxide (CO) and / from fascinat- problems in pharmacotherapy and sensitivity to chemical ing and beneficial viewpoints with respect to therapeutic exposure. targets. In addition, a new insight has postulated that HO The induction of P450s by drugs and chemicals is systems possess non-canonical functions with enzymat- usually coordinately accompanied by the induction of ic activities, such as shaperon-like roles in -pro- ALAS1 in order to supply heme for the newly synthesized tein interactions with P450s and others, and roles in intra- prosthetic group to the enzyme. On the contrary, HO-1, cellular compartmentalization and extracellular excretion an inducible form, up-regulation by pathophysiological (Vanella et al., 2016). In addition, reviews have appeared conditions or chemical insults leads to loss of P450s in on the beneficial and unfavorable evaluation of physiolog- the liver (Farombi and Surh, 2006). However, there are ical and pathological roles played by protoporphyrin IX, exceptions of such coordinated changes in P450s and intermediates of heme synthesis (Sachar et al., 2016) and heme metabolism, and reciprocal changes between HO-1 bilirubin, a heme degradation product (Zahir et al., 2015), induction and loss of P450s. Namely, some compounds in the body. Interestingly, Gao et al. (2017) most recent- can induce both P450s and HO-1, and others induce ly reported that plasma HO-1 is a potential hepatotoxic HO-1 together with CYP2A5 irrespective of whether oth- biomarker in rats when examined for acetaminophen-in- er basal P450s are decreased in the liver. Collectively, the duced hepatotoxicity. mechanistic features of a single chemical compound on The readers of this journal who are interested in phar- the induction and/or inhibition of heme metabolism and macologic application or toxicological manifestation of P450s are very complicated; the observed data should be the HO-1 system and its related physiological substanc- carefully evaluated. es will gain current understanding on pleiotropic cellular Experimental studies to clarify interplay between heme effects and multi-functional roles of this system. metabolism and P450s produced by chemical compounds in the liver have been carried out extensively to date; HEME SYNTHESIS, DEGRADATION, therefore, this review is focused on the possible inter- AND P450 SYNTHESIS IN THE LIVER play between the changes in heme synthesis and degrada- tion, and their interrelation to changes in P450 synthesis Figure 1 represents the pathways of heme biosynthe- caused by chemical compounds. sis and degradation, and its relation to P450 synthesis HO was firstly reported by Tenhunen et al. (1968) (Ponka, 1999). and has been thought to play an oxidative metabol- ic role in heme breakdown. Soon after the discovery of HEME SYNTHESIS the substrate for induction of HO-1, a line of evidence has shown that metal ions such as Co, metalloporphy- As illustrated in Fig. 1, eight enzymes are involved in rins, , many other pharmaceutical and heme biosynthesis, starting from condensation of succi- environmental chemical compounds, endogenous sub- nyl CoA and glycine to ALA by ALAS, a first and rate- stances, and hormones are inducers of HO-1 (Maines limiting enzyme in heme synthesis. Then ALA exports and Kappas, 1975; Maines, 1992, 1997 and therein; Surh to cytosol, where intermediates are stepwise and his colleagues, 2003, 2008; Ferrándiz and Devesa, synthesized and the intermediate coproporphyrinogen is

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Chemical-induced changes in hepatic heme and cytochrome P450

Fig. 1. Simplifi ed schematic diagram of heme metabolism and cytochrome P450 synthesis.

imported into mitochondria, and fi nally protoporphyrin IX enzymes are beyond the scope of this review, but readers is chelated with Fe2+ by to become heme. of this journal can refer to detailed information in another The newly synthesized heme exports to cytosol and is uti- review (Layer et al., 2010). lized for the synthesis of P450s and other various hemo- Evidence has been accumulated that porphyrin inter- . It is generally reported that almost 80% of heme mediates and heme are imported and exported through in the body is synthesized in , 15% in the transporters resides in mitochondria. Furthermore, Vinchi liver, and the remainder in other tissues. Almost over 50% et al. (2014) have revealed that plasma membrane heme of heme synthesized in the liver has been calculated to be transporter of hematopoietic cells feline leukemia virus utilized for the synthesis of P450s. This heme biosynthet- subgroup cellular receptor 1a (Flvcr1a) is expressed in ic pathway is fi nely controlled by feedback inhibition by mitochondria and plasma membranes in hepatic cells. the end-product heme at the step of ALAS, so as to main- They found that Flvcr1a maintains a free heme pool that tain so-called “free or regulatory pool” to keep safe levels regulates heme synthesis and degradation as well as P450 in the hepatic cells, since heme itself is pro-oxidant and expression. The fi ndings suggest that heme synthesis and toxic to cells. breakdown are regulated and maintained in a multiple The effects of P450-inducing lipophilic drugs such as ways in addition to the control of P450 synthesis. (PB) and on ALAS1 transcrip- tion have been shown to be mediated by -sens- HEME DEGRADATION AND ITS ing nuclear receptors, constitutive androstane receptor REGULATORY MACHINERY (CAR) and pregnane X receptor in the liver of humans and rodents (Fraser et al., 2003; Podvinec et al., 2004; Excess amount of heme is oxidatively catabolized by Fisher et al., 2007). HO. HO, whose existence was fi rst elucidated to be local- In addition to ALAS, the of the enzymes ized on microsomes (Tenhunen et al., 1968), has been involved in heme synthesis have been cloned and the determined to be also localized on the mitochondrial inner details of the expressed proteins are examined. However, membrane (Bansal et al., 2013; Converso et al., 2006). the genetic aspects and clinical manifestations on these As shown in Fig. 1, HO as a first and rate-limiting

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T. Yoshida et al. enzyme catalyzes heme into CO, biliverdin (reduced and traverses into the nucleus. In the nucleus, Nrf2 forms quickly to bilirubin by ) and Fe2+. heterodimers with small Maf proteins, subsequently these HO consists of three isoforms, HO-1 (an inducible form), heterodimers bind to cis-acting antioxidant responsive HO-2 (a constitutive form) and HO-3 (unknown func- element (ARE) and transcriptionally stimulate the pro- tion). HO-1 has been shown to be regulated by complex duction of a battery of genes encoded HO-1, phase 2 intracellular signaling cascades. To date, extensive stud- drug metabolizing enzymes such as glutathione S-trans- ies have been conducted on the regulation of HO-1 up- ferase (GST) and NAD(P)H:quinone -1 regulation and so many excellent reviews have been pub- (NQO1), anti-oxidative enzymes (Surh et al., 2008; Itoh lished (Maines et al., 1986; Maines, 1992, 1997; Kikuchi et al., 1999; Suzuki and Yamamoto, 2015; Keum and et al., 2005; Prawan et al., 2005; Vlahakis et al., 2006, Choi, 2014; Tebay et al., 2015). Thus, Keap1 performs 2009; Pittalà, 2013). Briefly, HO-1 expression is as a repressor of HO-1 and other enzymes in the cytosol. mediated by many transcription factors, such as nucle- Since Keap1 is a cysteine-rich multi-domain zinc metallo- ar factor E2-related factor-2 (Nrf2), activator protein-1 protein, modifi cation or oxidation by electrophilic chem- (AP-1), and nuclear factor-kappa B (NF-κB), and some of ical compounds of one of critical cysteine residues can their up-stream kinases, such as mitogen-activated protein lead to release of Nrf2, and thus up-regulate HO-1 and kinases, phosphatidylinositol 3-kinase, and protein kinas- anti-oxidative gene expressions (Numazawa and Yoshida, es A and C. The activation of these kinases by chemical 2004; Surh, 2003; Surh et al., 2008). Therefore, up-regu- electrophiles can directly cause phosphorylation of Nrf2 lation of Nrf2 is targeting for phytochemicals to maintain at serine or residue, and thus lead to the up-reg- health care and clinical applications. Many phytochem- ulation of HO-1. icals from plant and dietary components which induce At present, Nrf2 is well known as a positive regula- HO-1 have been shown to inhibit chemical carcinogene- tor of HO-1 and other many anti-oxidative and Phase II sis, and these phytochemicals are termed chemopreven- detoxifying enzyme genes. Under physiological condi- tive agents (Surh, 2003; Prawan et al., 2005; Saito 2013; tions, Nrf2 is retained in the cytosol as an inactive form Tebay et al., 2015). with Kelch-like ECH-associated protein 1 (Keap1) in Figure 2 depicts regulation of HO-1 induction by a very short half-life. When cells are exposed to elec- Keap1-Nrf2 system. At many steps, HO-1 is induced as trophilic chemicals, reactive oxygen species (ROS) and/ described above. On the other hand, basic leucine zipper or reactive nitrogen species, Nrf2 releases from Keap1 transcriptional factor 1 (Bach1) is another transcriptional

Fig. 2. Regulation of HO-1 induction by Keap1-Nrf2 pathway.

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Chemical-induced changes in hepatic heme and cytochrome P450 repressor of HO-1 on the ARE. Bach1 is also involved in P450s or influence heme metabolism. The drugs suspect- heme-mediated up-regulation of HO-1. In fact, the equi- ed to precipitate porphyria are anti-anxiety drugs glu- librium between Bach1 and Nrf2 in the nucleus regu- thetimide and meprobamate, diuretics spironolactone and lates ARE-dependent gene transcription. Because Bach1 hydralazine, progesterone and synthesized progestines, is cysteine-rich , modification of critical analgesics propoxyfen and dicrofenac, local cysteine can alter HO-1 gene activation (Itoh et al., 1999; lidocaine, anti-epileptics , phenytoin and val- Ishikawa et al., 2005; Davudian et al., 2016). proic acid, chloramphenicol, erythromycin, , Currently, HO-1 expression has been report- , sulfonamides and so on. Therefore, it is nec- ed as an important protective endogenous mechanism essary to understand the properties of prescription drugs against physical, chemical, and biological stress. In this in terms of whether they attack acute porphyrias (Thunell regard, HO-1 induction has been shown to have beneficial et al., 2007; Szlendak et al., 2016). Experimentally well- protective effects on several pathologic conditions, such known prototype chemical inducers of ALAS1 are as fol- as inflammatory processes, atherosclerosis, - lows: esis, ischemia-reperfusion systems, or degenerative dis- eases. HO-mediated breakdown products of biliverdin, 1) 2-allyl-2-isopropylacetamide (AIA) and similar which is rapidly reduced to bilirubin by biliverdin reduct- olefinic compounds which are suicide type sub- ase, CO and Fe2+, are now recognized as playing impor- strate of P450s. tant physiological, pharmacological, and toxicological 2) 4-Dicarbethoxy-2, 4, 6-trimethyl-1, 4-dihydro- roles in cells and tissues (Fig. 1). Specifically, CO as a pyridine (DDC) and its 4-ethyl analog of 4-ethyl- gas transducer plays a wide variety of important roles in DDC); these compounds also form N-alkylated physiological and pathological conditions (Wu and Wang, protoporpyrin which are potent inhibitory effect on 2005; Ryter et al., 2006; Ryter and Choi, 2016). Fe2+ is a ferrochelatase (De Matteis et al., 1980). strong oxidant in the presence of O2, thus it controls fer- 3) Tetrachlorodibenzo-p-dioxin (TCDD) and various ritin synthesis so as to keep safe and adequate levels. Fe2+ polyhalogenated biphenyls. is also reutilized for synthesizing heme. Bilirubin is gen- erally metabolized by conjugation reaction catalyzed by It is noteworthy to point out that there are exception- UDP- 1A1 (UGT) to glucuronide al cases of suicide-type ligands of P450s in which the conjugate and excreted to the . Interestingly, bilirubin P450s modified by the chemicals do not leave their heme was recently identified to be the endogenous substrate of moiety, and thus do not greatly affect ALAS1 levels as CYP2A5 (human homologue CYP2A6), which is induced described above. These are SKF-525A, metyrapone, and under hepatic pathophysiological conditions, hepatotox- macrolide such as oleandomycin, triacetylole- ic insults by chemical compounds (Kim et al., 2013). andomycin, and erythromycin. Accordingly, CYP2A5 has a role in controlling cellular The P450 induction carried out in our laboratory bilirubin levels by oxidation to biliverdin together with its was phenobarbital (PB)-mediated induction of CYP2B important enzymatic activity on toxic compounds of nic- and CYP3A together with the regulation of CAR. As otine, aflatoxins, and . For more details, Correia described above, it is well known that PB is an inducer of et al. (2011) have comprehensively reviewed regulation ALAS1 and P450s. The induction of P450s by PB is due of P450s in relation to the interplay between heme metab- to its activation of CAR (Hernandez et al., 2009). Shindo olism from various aspects of protein synthesis, assembly, et al. (2007) revealed that PB activates CAR, at least part- repair, and disposal. ly, in an AMP-activated protein kinase (AMPK)-depend- ent manner. However, the precise mechanisms underly- EFFECTS OF CHEMICALS ON HEME ing PB-mediated activation of AMPK are still unclear. SYNTHESIS AND INDUCTION OF P450S During the course of experiments to clarify PB-mediat- ed AMPK activation, Shizu et al. (2012) found significant To date, accumulating evidence has revealed that decrease in miR-122, a liver-rich micro RNA involved in a wide variety of drugs and chemicals which cause the both hepatic differentiation and function. The time-course increase of P450 synthesis (De Matteis and Marks, 1996; change in the PB-mediated down-regulation of miR- Kong et al., 2001; Xu et al., 2005), coordinately induce 122 was inversely correlated with AMPK activation. PB ALAS1 and perturb heme synthesis or inhibition. There- decreased primary miR-122 to approximately 25% of the fore, genetically well-known inherited disease porphyria basal level as early as 1 hr and suppressed trans-activi- in humans will be attacked by drugs which could induce ty of mir-122 promoter in HuH-7 cells, suggesting that

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T. Yoshida et al. the down-regulation occurred at the transcriptional lev- factors were involved in current signal transductions. el. AMPK activators did not produce any effect on miR- 122 levels, but an inhibitory RNA specific for miR-122 HO-1 INDUCTION AND ITS ENZYMATIC increased the activated AMPK and CAR-mediated trans- REACTION PRODUCTS activation. These and other results indicate that PB-medi- ated down-regulation of miR-122 is an early and impor- Excess amount of heme has been shown to be oxida- tant event in the AMPK-dependent CAR activation and tively metabolized by HO, producing biliverdin (reduced trans-activation of its target genes. Shizu et al. (2013) also to bilirubin by biliverdin reductase), Fe2+ and CO, as revealed that the cross-talk between CAR and hypoxia-in- shown in Fig. 1. Heme also down-regulates ALAS1 by ducible factor in the regulation of pro- the mechanisms at the transcriptional, translational or duced by PB. Thus, even in the well-known inducer of post-translational step in the liver. These two processes PB, its detailed P450-inducing mechanisms still remain to contribute to the homeostasis of hepatic heme level. Such be determined. highly tuned catabolism of heme would be due to its oxi- As shown in Table 1, we found that many chemical dant property and subsequent damage to cells, and thus nitrogen-containing compounds of pyridine and/or imida- importantly contributes to the homeostasis of its hepatic zole moieties are able to increase P450 content, and some levels of free and bound-type in living organisms. of them also induce ALAS1 in the rat liver, depending As shown in Fig. 1, the HO system, along with its on their abilities to induce the hemoproteins (Kobayashi reaction products, biliverdin/bilirubin, ferrous ion Fe2+ et al., 1992, 1993a, 1993b, 1994, 1995, 2001, 2002; and CO, have been recently recognized to be involved in Matsuura et al., 1991; Yoshida et al., 1995). Therefore, it a wide variety of crucial physiological functions, includ- is reasonable to say that P450 inducers are also inducers of ing cytoprotection, inflammation, anti-oxidative effects, ALAS1 in the liver. In turn, some of these compounds also apoptosis, neuro-modulation, immune-modulation, ang- induce HO-1 in a dose-dependent manner. The details of the iogenesis, and vascular regulation (Ryter et al., 2006; effects of nitrogen-containing compounds and their effects Ryter and Choi, 2016). Since HO-1 is ubiquitously dis- on ALAS1 and P450s will be presented later, but the mech- tributed in all tissues, HO-1 and its enzymatic products anisms have not been clarified with respect to what kinds of are linked to cytoprotective effects on oxidative damag-

Table 1. HO-1 inducers and inhibitors. Inducers • Fe-protoporphyrin (PP) (, , Methaemalbumin), Heme-arginine • Pharmaceuticals: , cis-Platinum, Pacritaxel, Probuchol, Rapamycin, Sildenafil, (NO) and NO releasing molecule, (CO) and CO releasing molecule, Deferroxamin, Phenobaribital (in cases of selelnium-deficient animals) • Metals: Cd, Co, As, Se, etc. • Metalloporphyrins: Co-PP • Phytochemicals (antioxidative compounds): , Quercetin, Epigallocathechingallate, Isothiocyanates, Sulforaphan, , etc.

Inducers examined by the authors • Metals and Metalloporphyrins (Cd, Co, Hemin, Co-PP) • GSH depletors (Diethylmaleate, Phorone, Various α,β-unsaturated carbonyl compounds) • Stilbene compounds (trans-, cis-stilbene, and their oxides) • Pyridines, Azoles, and Other nitrogen-containing compounds • Immunopotentiators (BCG, OK-432) • 4-Hydroxynonenal (a physiological end product of peroxidation) • 2,5-Hihydroxymethyl cinnamate, Hydroquinone • Lipopolysaccharide, Acetaminophen (in case of hepatptoxicity) • Auranofin (antirheumatoid drug)

Inhibitors • Metalloporphyrins: Sn-PP, Zn-PP, Zn-mesoporphyrin, Cr-PP, Cr-deuteroporphyrin • Organic compounds: Azalanstat, Imodazole-ioxilane derivatives

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Chemical-induced changes in hepatic heme and cytochrome P450 es in various tissues. Evidence is also accumulating that Additionally, they have shown that the well-known inhib- HO-1 induction and the resultant reaction products in itory ligands of P450s, such as SKF525A, metyrapone acute and chronic hepatic inflammation of rodent models and others, prevented such loss of P450s caused by the resulted in improvement of damage and down-regulation administration of Co and other HO-1 inducers, without of pro-inflammatory cytokine levels. Such experimental preventing the enzyme-inducing abilities of the inducers conditions have also interfered with fibrosis progression (Drummond et al., 1982; Hockin and Paine, 1983). All of and partially resolved existing fibrosis (Sass et al., 2012). these results indicate that radioactivity is originating from Discussions on possible therapeutically important roles of 14C-ALA-prelabeled P450 heme under the increase in HO-1 induction in many diseases are beyond the scopes HO-1 by the administration of drugs and chemicals. The of this review; however, many excellent reviews have mechanism-based inhibition of CYP3A4 by macrolide currently been published on this topic, including some in antibiotics, such as oleandomycin and troleandomycin, is this journal (Abraham and Kappas, 2008; Maines, 1992; also such stable examples for escaping from breakdown Farombi and Surh, 2006; Wegiel et al., 2014; Hoetzel and of its heme moiety by the HO-1 system. This class of Schmidt, 2010; Paine et al., 2010; Sass et al., 2012; Ryter macrolide antibiotics can accumulate CYP3A4 in hepat- and Choi, 2016). However, the increased heme degrada- ic microsomes, and thus exacerbate drug-drug interac- tion by the induction of HO-1 after the administration of tions in clinical uses. Furthermore, Mosterat et al. (2007) chemicals could lead to heme deficiency in the liver, thus have shown the increase in serum ion level in acute HO-1 leading to loss of P450s due to the decreased heme levels induction by PB in selenium-deficient mice, whose basal available for their replacement and synthesis. HO enzyme activity is increased by double or more com- Heme is an inducer of HO-1 and a repressor of ALAS1. pared to normal mice, although PB is a well-known pro- In turn, P450 inducers are ALAS1 inducers, and some totype inducer of P450s and Phase 2 enzymes. They have cases become HO-1 inducers in the liver as discussed lat- shown that the increases in serum 59Fe level were from er. Interestingly, PB, a prototype inducer of P450s, can the breakdown products of pre-labelled 59Fe-P450. It is induce HO-1 in selenium-deficient mice, which have of interest to note that PB induced HO-1 when adminis- increased basal level of HO-1 enzyme. Shizu et al. (2013) tered to selenium-deficient rats (Mostert et al., 2003a). have also shown that PB can induce P450s together with They have shown that selenium-deficient rats resulted in enzymes of hypoxia-inducible factor 1 (HIF1)-mediat- increased basal levels of HO-1 activity in the liver and ed pathways, with cross-talk between CAR and HIF1α. hepatocytes, but not in the kidney, brain or testis. These Although it may not be the case in the liver, evidence rats responded well to PB with AP-1-mediated induction exists indicating that heme can induce CYP1A1, which of HO-1. The findings are well compatible to our previous accumulates in the cytosol of kidney and brain (Meyer et paper indicating that PB-type P450 inducer of trans-stil- al., 2002). These findings suggest that intracellular heme bene oxide (TSO) can utilize AP-1 for inducing HO-1 in regulates P450 synthesis in some tissues. the liver (Oguro et al., 1998). The turnover of prosthetic heme of P450s has been well recognized by using 14ALA- HO-1 INDUCTION AND LOSS OF P450S and 59Fe-prelabelled heme, and its rapid breakdown under IN THE LIVER HO-1 inducers as described above. On the other hand, what kind of mechanisms exist in It is well known that HO-1 induction contributes sig- the degradation of P450 protein moiety? It is well known nificantly to the decrease in P450 content observed after that hepatic (ER)-anchored P450s the administration of HO-1 inducers, such as Co, Cd, exhibit wide ranges of half-lives (around 7-38 hr) depend- metallopopyrins and so on. The clues of such decrease in ing on molecular species. The reasons for such differenc- P450s in hepatic microsomes after the induction of HO-1 es in their turnover have not been clearly determined. have been elucidated by De Matteis and colleagues (1975, Under physiological conditions, it has been suggest- 1976). They showed that the induction of HO-1 followed ed that protein molecules will be damaged during their the accelerated loss of 14C-ALA radioactivity from P450s own enzymatic activity by producing ROS and so on. In together with the increased radiolabeled bilirubin concen- this respect, CYP2E1, which produces high amounts of tration in the bile and its specific radioactivity. The losses ROS during its functional activity, shows rapid turnover of radioactivity from 14C-ALA-prelabeled liver homoge- compared to other species. In addition, P450s have been nates in fed and fasted animals were further enhanced by shown to incur phosphorylation at serine and/or threonine treatment with Fe-dextran or CoCl2, two powerful HO-1 residues. This post-translational modification of P450s is inducers, along with a significant loss of P450 content. likely to be a marking for degradation. Therefore, P450

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T. Yoshida et al. lifetime will be changed depending on its enzymatic a marked increase in CYP2A5 apoprotein with an unu- activities, receiving damage by ROS or other insults, and sually high affinity to heme may explain the increase in feasibility of post-modification etc. Apo-P450 enzymes the enzymatically active CYP2A5 in spite of cellular heme have been shown to undergo proteolytic degradation depletion under experimental conditions. The Cyp2a5 pro- by the 26S proteasomal route, rather than the lysosom- moter contains a "stress-responding" cluster of binding al route. However, as mentioned above, heme-saturated motifs, which interact with major mediators of toxic insults, P450 enzymes and specific substrate-bound enzymes are including Nrf2 and aryl hydrocarbon receptor (AhR). stable from proteolytic degradation, and thus such condi- Lämsä et al. (2010, 2012) have shown that hemin and tions are important determinants of P450 lifetimes. Co-protoporphyrin (PP) can induce CYP2A5 and HO-1, Currently, two distinct pathways have been identi- with the former case almost completely dependent on fied, one involving -dependent 26S proteaso- Nrf2 in mouse hepatocytes. Importantly, Abu-Bakar et al. mal disposal, the other relying on autophagic-lysosomal (2013) have revealed that CYP2A5 protein is stabilized degradation. Explanation of such important and interest- by bilirubin and is able to oxidize bilirubin to biliverdin. ing subjects on the destination of P450s is far beyond the Based on their findings, they postulated that CYP2A5 is scope of this review. To understand the important current an inducible bilirubin oxidase that may both prevent accu- knowledge of apo-P450 degradation mechanisms, please mulation of bilirubin in high cytotoxic levels in the liver refer to excellent reviews recently published by Correia et and delay its elimination from the liver. Likewise, human al. (2014) and Kim et al. (2016). CYP2A6 was shown to metabolize bilirubin to biliverdin (Abu-Bakar et al., 2013). The findings suggest that the CHEMICAL-INDUCED LIVER INJURY AND induction of CYP2A5 by chemical-mediated hepatotoxic CONCURRENT INDUCTION OF HO-1 AND insults acts to maintain cellular bilirubin homeostasis and CYP2A5 oxidative balance. We have also observed Nrf2-deficient (Nrf2−/−) mice Many drugs and chemicals have been shown to pro- to investigate the involvement of Nrf2 in CYP2B10 and duce liver injury either directly or by metabolic activa- CYP2A5 gene expression (Ashino et al., 2014). Phorone, tion (Nichols and Kirby, 2008). Current evidence indi- a GSH depletory, a HO-1 inducer (Oguro et al., 1996, cates that cytoprotective responses of HO-1 and CYP2A5 1997, 1998), and an Nrf2 activator, strongly increased induction occur against such hepatotoxic insults (Liu and CYP2B10 and CYP2A5 mRNA as well as Nrf2 target Qian, 2015). Kirby et al. (2011) have shown that induc- genes, including NQO1 and HO-1, in wild-type mouse tion of CYP2A5 in such hepatotoxic insults is an adaptive livers. Phorone-induced mRNA levels in Nrf2−/− mouse response to the perturbation of hepatic heme metabolism. livers were lower than that in wild-type mouse livers. In this respect, HO-1 induction through Nrf2-depend- Nrf2−/− mice showed attenuated CYP2B10 and CYP2A5 ent manner has been extensively studied to date. Under induction by PB, a classical CYP2B inducer (Ashino et the conditions where HO-1 is induced, hepatic P450s are al., 2014). These findings suggest that the Nrf2 pathway generally being decreased as described above. However, is involved in CYP2B10 and CYP2A5 gene expression. murine CYP2A5 has been shown to be induced by hepa- The CYP2A5 promoter contains a "stress-responding" totoxic agents, together with the induction of HO-1 by the cluster of binding motifs, which interact with major medi- administration of a wide variety of HO-1 inducers, such ators of toxic insults, including Nrf2 and AhR. Therefore, as metals (Pb, Cd, etc.), metalloporphyrins, oxidants, eth- concurrent induction of HO-1 and CYP2A5 will be rea- anol, bilirubin, and toxic agents (chloroform, thioaceta- sonably observable phenomena. However, it should be mide, pyrazole, aminotriazole, etc.) and also under the kept in mind that regulation of CYP2A5 and its ortholog conditions of and so on. (Camus-Randon CYP2A6 differs somewhat between animals and humans, et al., 1996; Lämsä et al., 2010, 2012). Thus, CYP2A5 since both gene expressions respond differently to chem- induction in the liver is an exception to other P450s with icals, including lack of response in the human gene, etc. respect to the response to HO-1 inducers. The reasons for (Su and Ding, 2004). such a unique response of CYP2A5 to HO-1 inducers and hepatotoxic stimuli in the liver have been shown to be due EFFECTS OF NITROGEN-CONTAINING to its regulatory machinery. Namely, Nichols and Kirby COMPOUNDS ON P450 SYNTHESIS AND (2008) have shown that transcription of CYP2A5 gene is HO-1 INDUCTION stimulated by oxidative stress in an Nrf2-dependent man- ner, as in the case of the HO-1 gene. They indicated that N-substituted imidazole- and pyridine-ring-contain-

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Chemical-induced changes in hepatic heme and cytochrome P450 ing compounds have sometimes been shown to induce or tional structures are potent inducers of CYP1A1/2. inhibit P450s in animal and human livers. We have exam- Kobayashi et al. (2000) also found that 2,2'-dipyridyl ined various types of nitrogen-containing compounds ketone and 2,2'-dipyridyl amine induced hepatic micro- with regard to P450 synthesis and HO-1 induction. Those somal P450s and HO-1, and examined their effects on are pyridine, dipyridyl and imidazole structures which different P450 isoforms (P4501A1, 3A2, 2B1 2E1, and are able to induce P450s, and some of them also induce 2C11) in rats. 2,2'-Dipyridyl amine resulted in the marked ALAS1 in the rat liver, depending on their abilities to induction of HO-1 with a decrease in P450 content. 2,2'- induce the hemoproteins (Kobayashi et al., 1992, 1993, Dipyridyl ketone produced concomitant induction of both 1994, 1995; Matsuura et al., 1991; Yoshida et al., 1995). P450 and HO-1 in a dose- and time-dependent manner. On this occasion, our retrospective experimental results Immunoblot analysis revealed that 2,2'-dipyridyl ketone are presented and discussed. slightly increased CYP2E1 and CYP3A2 at low dos- Matsuura et al. (1991) examined and es, but not at high dose levels. There was no effect on structurally related compounds and found the significant CYP2C11. CYP2B1 was induced by treatment with 2,2'- increases in P450 content in the liver. Azole compounds dipyridyl ketone in a dose-dependent manner. Dipyridyl are generally induced P450s depending on the position compounds having different bridges between two aromat- of the rings. 4-Benzylpyridine and related compounds ic moieties act as differential inducers of P450s and HO-1. (Kobayashi et al., 1992), imidazole and pyridine relat- In addition, dipyridyl isomers, produced differentially on ed compounds (Kobayashi et al., 1993a) and 1-benzylim- HO-1 and P450s (Kobayashi et al., 2000). 2,2'-Dipyridyl idazole (Kobayashi et al., 1993b) have investigated to increased P450 content at lower doses, but decreased with find the structural requirements for the induction of CYP increasing dose levels. Immunoblot analysis revealed that 2B1/2 and CYP1A1/2 in rats. As a whole, clotrimazole, 2,2'-dipyridyl did not induce CYP1A1/2 and CYP2B1/2, an azole drug, and 1-diphenylmethylimidazole in contrast to 2,4'- and 4,4'-dipyridyls, both of which preferentially induced CYP2B1/2 in a dose-dependent induced either CYP1A1/2 and/or CYP2B1/2. 2,2'-Dipy- manner, and slightly induced CYP1A1/2. 1-Benzylimi- ridyl induced HO-1 in a dose-dependent manner, but dazole preferentially induced CYP1A1/2. 1-Phenylimida- 2,4'- and 4,4'-dipyridyls did not. The induction of HO-1 zole, which lacks the methylene bridge of 1-benzylimida- by 2,2'-dipyridyl was preceded by the early decrease in zole, only induced CYP1A1/2. In turn, loss of aromatic hepatic GSH content, just as observed in GSH deple- moiety of the N-substituted imidazole, as in 1-cyclohex- tors (Oguro et al., 1996, 1998; Yoshida et al., 1995). The ylmethylimidazole and 1-tert-butylimidazole, resulted present investigation has revealed that in contrast to the in a preferential induction of CYP2B1/2. Likewise, var- induction of P450 by 4-substituted dipyridyl compounds, ious pyridine-containing compounds showed structure- 2,2'-dipyridyl is a novel inducer of HO-1 in the liver, dependent induction of P450 species. Namely, 4-diphe- together with the change in hepatic GSH content. This nylmethylpyridine induced CYP2B1/2. 4-Benzylpyridine study may provide information on the differential effects induced both CYP2B1/2 and 1A1/2. 4-Cyclohexylmethyl- of simple dipyridyl isomers on hepatic enzymes involved pyridine and 4-tert-butylpyridine predominantly induced in heme and . In addition, we also found CYP2B1/2. 4-Phenylpyridine preferentially induced that climbazole potently induced CYP2B1, 3A2 and 4A1, CYP1A1/2 rather than CYP2B1/2. Oxygenation prod- and UGT and GST in rats (Kobayashi et al., 2001, 2002). ucts at the methylene bridge in 4-benzylpyridine, 4-ben- zoylpyridine and phenyl-4-pyridylmethanol, could not STILBENE COMPOUND-PRODUCED CHANGES induce CYP1A1/2. In turn, 2,4'-dipyridyl induced both IN P450S, ALAS1, TRANSPORTERS AND HO-1 CYP2B1/2 and CYP1A1/2, but not 2,2'-dipyridyl. 4,4'- BY MEDIATING MULTIPLE TRANSCRIPTIONAL Trimethylenedipyridine preferentially induced CYP1A1/2 FACTORS IN THE LIVER at very low doses. In the case of 4-phenylalkylpyridine (chain length of 0-5, 7, 9 and 11 carbon atoms), P450-in- Resveratrol is one of the naturally occurring and well- ducing abilities were significantly changed depending on known stilbenoids. Resveratrol is now extensively exam- chain length, decreasing with the longer chains. In female ined for its health benefit activities, and is a very com- rats, there was no chain length-dependent induction of mon constituent in our diet and nutritional supplements. CYP1A1. These findings indicate that imidazole- and Accordingly, benefit of resveratrol has been expected to pyridine-containing compounds having lipophilic groups promise in the treatment of various chronic diseases, such are inducers of hepatic P450s, and that such compounds as cancer, diabetes, neurodegeneration, and cardiovas- having aromatic groups and taking coplanar conforma- cular disease. Such beneficial effects of resveratrol have

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T. Yoshida et al. been explained by its pleiotropic targeting on many tran- HO-1 and P450 regulation in rats. scriptional factors of Nrf2, AP-1, Egr1, Elk1, etc. Resver- Likewise, Slitt et al. (2006a, 2006b) have shown that atrol-induced activation of the former two transcription- TSO induces drug-metabolizing enzymes in rat and mouse al factors could lead to up-regulation of the HO-1 system liver via CAR activation. TSO also increased expressions as discussed in this review. However, it should be noted of various enzymes, such as Cyp2b10, NQO1, epoxide that transcriptional targets of resveratrol have been main- , HO-1, UDP-glucuronosyltransferase (Ugt) ly elucidated in in vitro studies. Since there are so many 1a6 and 2b5, and multidrug resistance-associated pro- reviews published on resveratrol to date, we cited and teins (Mrp) 2 and 3 mRNAs in livers from male mice, but focused on only recent reviews for mechanistic insight not Nqo1 and Mrp3 expression in CAR-null. The findings and its effects on the liver (Faghihzadeh et al., 2015; clearly indicate that TSO induces Cyp2b10 and epoxide McGill et al., 2015; Thiel and Rössler, 2016). hydrolase via CAR, but both were not changed in livers With respect to stilbene compounds, trans-stilbene from wild-type and CAR-null mice. They also showed (TS) is considered to be a PB-like compound because that TSO increased nuclear staining of Nrf2 in the liv- it induces CYP2B mRNA and protein in animal livers. er, and activated ARE. Thus, a single compound can acti- Interestingly, TSO and its cis-configuration of CSO pro- vate both CAR and Nrf2 transcription factors in the liver duced a reciprocal relationship among induction of P450s, (Merrell et al., 2008). ALAS1 and HO-1 in a dose-dependent manner (Matsuura Most recently, Kosuru et al. (2016) have comprehen- et al., 1988; Oguro et al., 1997). At relatively low doses, sively reviewed that preclinical and experimental stud- both TSO and CSO induced P450s, while with increas- ies on promising therapeutic potentials of pterostilbene ing doses they instead reduced P450 content. High dos- in view of mechanistic basis. Pterostilbene is a natural- es of TSO significantly reduced hepatic GSH content. ly occurring of stilbenoids. Its chemical This may lead to oxidative stress in the liver, and thus structure is a dimethoxy compound of resveratrol which produce the increase in Nrf2-related responses (Walsh et has multifunctional activities by Nrf2-dependent mecha- al., 2014). The clues for the depletion of GSH were pre- nisms. Kosuru et al. (2016) have summarized the sources treatment of rats with buthioninesulfoximine (BSO), an (blueberries, grape wines, etc.), pharmacokinetic aspects, inhibitor of GSH biosynthesis, enhanced GSH deple- pharmacodynamics of pterostilbene with molecular mech- tion evoked by either TSO or CSO and augmented the anisms underlying its protective and beneficial effects increase in HO-1 mRNA. In contrast, pretreatment with against various diseases, such as cancer, dyslipidemia, perfluorodecanoic acid (PFDA), which reduced hepat- diabetes, and cardiovascular and central nervous system ic GSH S- activity, prevented TSO- and CSO- disorders. Based on the presently available evidence, they mediated GSH depletion and abolished HO-1 induc- concluded that pterostilbene is a safe and active phytonu- tion. In addition, TSO and CSO enhanced c-jun but not trient and a potential drug with pleiotropic health applica- c-fos mRNA, which is in parallel with the HO-1 mRNA tions. Pterostilbene is also shown to be superior to resver- change. These findings indicate that the oxidative stress atrol from the view point of bioavailability in the body. evoked by GSH depletion by TSO and CSO could stim- One of the well-known mechanisms of the beneficial ulate both HO-1 and c-jun gene expression. Pretreatment effects of ptreostilbene is Nrf2-dependent anti-oxidative with either BSO or PFDA also affected the induction of cytoprotection. CYP2B1/2 mRNA and apoprotein by TSO or CSO, sug- As described above, naturally occurring stilbenoids gesting that not only the change of heme pool size but and synthesized stilbene compounds represent a wide also some other unknown factors may be involved in the variety of activities in the body by mediating many tran- regulation of the CYP2B1/2 and HO-1 gene expression. scription factors. The review summarized by Kosuru et cis-Stilbene (CS), also induced HO-1 mRNA, together al. (2016) presents an example of how a single phyto- with hepatic GSH depletion, but not TS. In addition, CS chemical compound produces a multifaceted and pleio- increased CYP2B1/2 mRNA, whereas TS did not. These tropic activity in organs and tissues. Thus, how the body results suggest that CS could be rapidly metabolized and controls the changes in these various factors when long- oxidized by P450s to CSO, leading to GSH depletion in term treatment with this kind of compound remains to be the liver. Like other PB-type P450 inducers, TSO and elucidated. The recent approval of Nrf2 activator dime- CSO also induced CYP2C6 and 3A2 apoproteins in rat thyl fumarate for the treatment of multiple sclerosis has liver. TSO instead reduced CYP2E1 mRNA and apopro- emphasized the importance of this in teins for CYP2E1 and 2C11. All of these findings indicate regulating cellular defense mechanisms against oxidative that stilbene compounds have unique effects on hepatic stress in diseases (Linker and Gold, 2013).

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In addition to stilbenoids, various naturally occurring CHRONIC EFFECT OF DRUGS ON HEME phytochemicals having multifaceted abilities with medi- METABOLISM ating various transcriptional factors, such as Nrf2 and CAR, have been examined extensively to date. These Isoniazide (INH) is a well-known anti-tuberculosis include glucosinolates (Fuentes et al., 2015), curcuminoid drug and causes hepatotoxicity in patients and experimen- (Prasad et al., 2014), organic sulfur compounds from tal animals. It has been shown that chronic treatment of garlic oil such as diallyl sulfide (Rao et al., 2015). All mice with INH causes protoporphyrin IX accumulation of these naturally occurring phytochemicals have been in the liver, together with the induction of ALAS1 and extended as nutriceuticals. downregulation of ferrochelatase (Sachar et al., 2016). As depicted in Fig. 1, the results obtained from chronic treat- PB AS AN INDUCER OF HO-1 IN ment of mice with INH clearly indicate that loss of feed- SELENIUM-DEFICIENT ANIMALS back regulation by the lack of end-product heme readily leads to the accumulation of protoporphyrin IX in the liv- PB is a well-known prototype inducer of phase-1, er, and causes hepatotoxicity. This intermediate-induced phase-2 and transporters and others. Additionally, accumulation of protoporphyrin IX in human porphyrias PB induces HO-1 in selenium-deficient mice and rats can cause skin photosensitivity, biliary stones, hepatobil- (Mostert et al., 2003a, 2003b, 2007). Selenium-deficient iary damage, and even liver failure. On the other hand, mice, which lack thioredoxin reductase and other sele- protoporphyrin IX-based strategies have been employed noenzymes, such as GSH -1 etc., showed a for cancer diagnosis and treatment. In this respect, the doubling of HO activity compared with the control, and recently published review by Sachar et al. (2016) exam- further increased both HO-1 protein and mRNA levels by ines physiological and pathological activities of protopor- the administration of PB. They also showed that the treat- phyrin IX. ment of control mice with aurothioglucose, an inhibitor of thioredoxin reductase, resulted in an increase in HO-1 HO INHIBITORS and further augmented by PB administration, suggesting that loss of thioredoxin reductase in selenium-deficient As described above, Nrf2-Keap1-regulated HO-1 mice has a key role in HO-1 induction. This induction induction has been shown to be an important defense of HO-1 by PB occurred in hepatocytes but not Kupffer mechanism against pathophysiological conditions or cells. These findings indicate that selenium deficiency chemical-induced hepatotoxicity. To date, widely diver- causes oxidative conditions in the liver, thus leading to gent HO-1 inducers have found and their abilities to activation of transcriptional factor AP-1-mediated induc- antagonize oxidative insults, disease modulations and tion of such stress responsive enzymes. With respect to chemoprevention for chemical carcinogenesis have been selenium-deficient animals, Burk et al. (2008) found the exploited. increase in Nrf2/ARE system and its regulatory enzymes In contrast, the number of HO inhibitors is very lim- of NQO1, HO-1 and GST. However, such an increase in ited to date. Historically, metalloporphyrins, such as Sn- the antioxidant responsive system did not occur with vita- and Zn-PP, and Cr-deuteroporphyrin shown in Table 1, min E deficiency. In addition, deletion of Nrf2 abolished have been developed as HO inhibitors. Some of them GST induction but not NQO1 and HO-1, suggesting the have been therapeutically applied to hyperbilirubinemia oxidant defense mechanisms in which these antioxidant and certain types of cancer (Maines, 1992). Our study nutrients function are independent of one another. Also, using metalloporphyrins revealed that although pretreat- the increase in anti-oxidative defense factor Nrf2/ARE ment with Co-PP inhibits LPS-mediated induction of in Se-deficiency probably highly sensitizes to chemical- inducible gene expression, Sn-PP ly-mediated hepatic insults such that PB which induced does not have its inhibitory effect, suggesting the impor- HO-1 and other stress responsive enzymes, as report- tance of HO-1 activity in the inhibition of immunostimu- ed by Mostert et al. (2003a, 2003b, 2007). However, the lation (Kinobe et al., 2008; Ashino et al., 2008). detailed mechanism for the induction of HO-1 by PB in Pittalà et al. (2013) have recently published a review selenium-deficient rodents remains to be determined. that highlights the historical advances in the field of HO-1 inhibitors, particularly from a medicinal chemistry point of view; the progress made in the field has strong- ly helped to clarify physiological roles of HO system. They have found that metalloporphyrins are non-selective

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T. Yoshida et al. inhibitors of HO when clinically or experimentally used cellular changes in time- and dose-dependent manners both in vivo and in vitro. In addition, some metallopor- by mediating different transcription factors. This review phyrins have been shown to inhibit other hemoproteins mainly focused on interplay between heme metabolism and P450 activities, and also have been exploited to acti- and P450s. As discussed in this review, chemical com- vate the HO-1 gene. Since enzymatically active HO con- pounds are able to produce a wide variety of pharmaco- sists of molecular species of HO-1 and HO-2, it is neces- logical and toxicological effects on experimental animal sary to develop isozyme selective inhibitor. tissues, specifically on livers. Vlahakis et al. (2006, 2008) synthesized imidazole-di- Current “omics” technology can clearly unveil chem- oxolane compounds and evaluated them as novel inhib- ical-induced multiple changes in the liver in time- and itors of HO. These compounds are structurally distinct dose-related manners. Such a comprehensive experi- from metalloporphyrin-type HO inhibitors. The newly mental approach will give toxicological scientists a wide synthesized compounds lack the aminothiophenol moie- range of data which should be understood and considered, ty of azalanstat which have been developed as a lanos- and will aid mechanistic clarification. terol 14α- inhibitor with a lowering effect on cholesterol (Burton et al., 1995). They have shown that ACKNOLEDGMENT these imidazole-ioxolane compounds are highly selective for HO-1 with very low inhibitory potency toward HO-2. The authors thank to old and current members of The development of such isozyme-selective HO inhibi- Division of Toxicology, Showa University School of tion would be very beneficial tool to clarify roles of the Pharmacy. Many paper cite in this review various places HO-1 system both in vitro and in vivo. have been carried out at the laboratory. The authors also To clarify the details of the roles of the HO system, congratulate 40 years Anniversary issue of J. Toxicol. enzymatic products of CO, bilirubin and Fe2+, and the Sci. from The Japansese Society of Toxicology. Finally, mechanisms underlying its physiological effects and path- the authors express special thanks to Dr. Kaji, an editor ological involvement, development of molecular selec- of Journal of Toxicological Sciences, for recommendation tive HO inhibitors has been required, expected and pro- and suggestion of our researches to publish on this jour- moted. It is also required that an HO inhibitor does not nal. interact with P450s and inhibit enzymatic activities, since drug-drug interactions will occur. From these aspects, Conflict of interest---- The authors declare that there is a selective inhibitor of HO-1 is generally preferable. In no conflict of interest. addition to a first generation of non-porphyrin-based, iso- zyme selective HO-1 inhibitors, a second generation of REFERENCES imidazole-dioxolane derivatives has been developed and these compounds are used experimentally for elucidating Abraham, N.G. and Kappas, A. (2008): Pharmacological and clini- an inhibitory effect on HO-1 both in in vivo and in vitro cal aspects of heme oxygenase. Pharmacol. Rev., 60, 79-127. Abu-Bakar, A., Hakkola, J., Juvonen, R., Rahnasto-Rilla, M., studies (Rahman et al., 2010). Raunio, H. and Lang, M.A. (2013): Function and regulation of Another emerging line of evidence requires fur- the Cyp2a5/CYP2A6 genes in response to toxic insults in the ther development of HO-1 inhibitors; some cancer liver. Curr. Drug Metab., 14, 137-150. cells, including carcinogenic hepatocytes, possess sta- Ashino, T., Ohkubo-Morita, H., Yamamoto, M., Yoshida, T. and bly increased status of Nrf2/Keap1 system with genetic Numazawa, S. 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