The Journal of Toxicological Sciences (J. Toxicol. Sci.) SP89 Vol.41, Special Issue, SP89-SP103, 2016 Review Chemical-induced coordinated and reciprocal changes in heme metabolism, cytochrome 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 enzymes, and of drug-metabolizing enzymes, including cytochrome P450s (P450s, CYPs), which consist of many molecular species with lower substrate specificity. Such chemi- cally induced enzyme 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 hemoproteins, 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 oxygenase-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, Heme oxygenase, 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 iron (Fe2+), and it serves as the prosthetic group (Ponka, 1999). Cellular heme levels are precisely tuned Correspondence: Takemi Yoshida (E-mail: [email protected]) Vol. 41 Special Issue SP90 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 cytochrome P450 (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 biliverdin/bilirubin 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 protein-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, phytochemicals, 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 porphyrin intermediates are stepwise and his colleagues, 2003, 2008; Ferrándiz and Devesa, synthesized and the intermediate coproporphyrinogen is Vol. 41 Special Issue SP91 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 ferrochelatase 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- proteins. It is generally reported that almost 80% of heme mediates and heme are imported and exported through in