Cytochrome P-450 Enzymes As Targets for Chemoprevention Against Chemical Carcinogenesis and Toxicity: Opportunities and Limitations1'2

ICANCKRRESEARCHISUPPL.)54.twis-ims. Aprili.i

Chung S. Yang,3 Theresa J. Smith, and Jun-Yan Hong

ry for Cancer Research, Collect' of Pharmacy, Rutgers University, I'iscataway, New Jerse

It is well established that most chemical carcinogens require met some of these compounds are shown in Fig. 1. The possible applica abolic activation before exerting their carcinogenic effects. The acti tion of these compounds for chemoprevention of carcinogenesis and vated carcinogens are usually electrophilic agents and are highly toxicity as well as possible problems associated with this approach reactive toward DNA molecules. DNA modifications, especially those will also be discussed. on oncogenes and tumor suppressor genes, are generally major driving forces for cancer development. In theory, chemical carcinogenesis can Effects of Allium Organosulfides on P450 Enzymes and be prevented, in most cases, by blocking the metabolic activation Carcinogenesis process. Since cytochrome P450 enzymes play key roles in the acti vation of most carcinogens (1, 2), the inhibition of P4504-dependent Our interest in garlic compounds was stimulated by the epidemio- carcinogen activation, especially by dietary chemicals, has been stud logical observations that frequent consumption of garlic and other ied extensively. It is also recognized that P450 enzymes play key roles allium vegetables was associated with lower incidence of gastric in the biotransformation of many important endogenous compounds cancer in certain areas (12, 13). The inhibitory action of DAS against and in the detoxification of numerous xenobiotics (1^1). Therefore, carcinogenesis induced by DMH and NMBzA has been reported by blocking P450 enzyme activities may not be a practical approach for Wargovich et al. (14, 15). The anticarcinogenic activity of related the prevention of carcinogenesis. allium organosulfides in other animal models has also been reported Alteration of P450 enzymes has been cited frequently in the liter by Wattenberg et al. (16, 17). Alteration of P450 Enzymes by Diallyl Sulfide. In order to un ature as a mechanism for the inhibitory action against carcinogenesis by certain chemicals. Statements such as "This compound is a che- derstand the influence of DAS on the activation of carcinogens, its effects on different P450 enzymes were studied in rats. After a p.o. mopreventive agent because it inhibits P450, an enzyme required for carcinogen activation" and "This compound is a chemopreventive dose of DAS (200 mg/kg), rats were sacrificed at different time points and microsomal P450 enzyme contents and activities were measured agent because it induces P450, an enzyme for the detoxification of carcinogens" are often cited. These statements may sometimes be (18). The treatment did not produce a significant change in the total hepatic P450 content or the NADPH:P450 oxidoreductase activity. misleading. In order to understand the activation of different carcin However, upon examining specific P450 enzymes, the PROD activity ogens as well as the inhibition of this process by various compounds, which was low in untreated rat liver microsomes was greatly in a clear understanding of the properties of different P450 enzymes is creased by DAS, reaching a plateau of 100-fold increase at 24 to 48 essential. Cytochrome P-450 enzymes are products of the CYP superfamily of h. Subsequent studies indicated that this increase in PROD activity was due to the induction of CYP 2BI gene at the transcriptional level genes. Over a hundred mammalian CYP genes have been cloned and (19, 20). On the other hand, a time-dependent decrease in P450 studied extensively (5). Although there are overlapping substrate 2E1-dependent NDMA demethylase activity was observed; the activ specificities among different P450 forms, distinct substrate selectivi- ity was lowest (20% of the control) at 15 h and gradually returned to ties have been demonstrated in many cases, especially when low the control level (1.4 nmol/min/mg protein) after 2 days (18). When substrate concentrations were used in the assay. For example, among DASO, was given to the rat, the NDMA demethylase activity de the three major P450 forms in human liver microsomes, P450 3A4, presumably with a large substrate-binding pocket, catalyzes the bio- creased very rapidly, observable at 10 min and decreased to 25% of the control at 2 h (18). DAS has also been shown to slightly decrease transformation of many drugs (1, 6); P450 2E1 with apparently a hepatic 16ÃŸ-testosterone hydroxylase activity (possibly due to P450 small substrate-binding pocket catalyzes the oxidation of many vol atile environmental chemicals and anesthetics (6-10); and P450 1A2 3A) ( 18). A similar inhibition of P450 2E1 by DAS was also observed with mice in which a slight decrease in EROD activity (mainly due to catalyzes the activation of carcinogenic arylamines and aflatoxin B, P450 1A2) was also observed.s (6, 11). It is also known that certain chemicals, many of which have Inhibition of P450 2E1 and Related Carcinogenesis by Diallyl a dietary origin, can inhibit the activities of these enzymes selectively Sulfide. Subsequent studies demonstrated that DAS was oxidized by (7), thus providing the opportunity for selective inhibition of the P450 enzymes and flavin-containing monooxygenases to DASO and carcinogenicity and toxicity ot known chemicals by specific inhibitors then to DASO,. DASO2 was further metabolized by P450 2E1 to a of P450 enzymes. The possible application of dietary chemicals in the reactive intermediate which could attack the heme moiety of the prevention of carcinogenesis will be illustrated herein with examples enzyme and inactivate P450 2E1 in a suicide inhibition mechanism. In based on our studies on DAS, a compound derived from garlic, PEITC, a compound derived from cruciferous vegetables, and fla- addition, DAS, DASO. and DASO, were all competitive inhibitors of P450 2E1 (21). When DAS was given acutely or chronically to rats for vonoids which occur widely in fruits and vegetables. The structures of 4 weeks, a decrease in the NDMA demethylase activity and P450 2E1 level were observed. DASO and DASO, together with elevated ace 1 Presented at the 4th International Conference on Anticarcinogenesis & Radiation tone levels were observed in the blood.5 This result is consistent with Protection. April IK-23. Baltimore. MD. -This study was supported by NIH Grants CA37Ãœ37, CA46535, ES05693, and the proposed role of P450 2E1 in the metabolic conversion of acetone National Institute of Environmental Health Sciences Center Cirant ES05022. to acetal and methylglyoxal which are intermediates of a gluconeo- 3 To whom requests for reprints should he addressed. 4 The abbreviations used arc: P450, cylochromc P-450; DAS, diallyl sulfide; PEITC, genic pathway from acetone (9, 22). Since P450 2E1 is vital in phenelhyl isothiocyanate: DMM, 1.2-dimethvlhydrazine; NMBzA. /V-nitrosomelhylbcn- catalyzing the activation of NDMA, alkanes, halogenatcd hydro- /ylamine: DASO,, diallyl sulfone: DASO, diallyl sulfoxide: PROD. 7-pentoxyresorufin O-dealkylase: NDMA. iV-nilrosodimelhylamine; NNK. 4-(melhylnilrosamino)-l-(3-pyr- idiyl)-I-butanone; EROD. 7-ethoxyresorufin O-deelhylasc: APAP. acetaminophen. 5Unpublished results. 1982s

Diallyl sulfide Diallyl sulfone Phenelhyl isothiocyanate

OCH,

Fig. 1. Structures of some compounds that are known to affect cytochromc P-450-dependent reac tions.

Quercetin Kaempferol Naringenin

carbons, and many other low molecular weight environmental chem Mechanisms of Inhibition of Tumorigenesis by Diallyl Sulfide icals (7, 9, 10), inhibition of P450 2E1 is expected to block the toxicity and Related Compounds. In addition to the inhibitory activity of and carcinogenicity of these compounds. The inhibition of P450 DAS against DMH-, NMBzA-, and NNK-induced tumorigenesis, 2El-dependent activation of carcinogens is the most likely molecular allyl mercaptan, diallyl disulfide, and dipropyl sulfide, which are not mechanism for the reported inhibitory action of DAS against DMH- effective P450 2E1 inactivators, were also effective in inhibiting induced hepatotoxicity and colon carcinogenesis in rats (14, 23). In /V-nitrosodiethylamine-induced tumorigenesis in the forestomach of the activation of DMH, the first intermediate is azoxymethane. He female A/J mice (16). Allyl methyl trisulfide, diallyl trisulfide, and patic P450 2E1 catalyzes the oxidation of azoxymethane to methyla- DAS, when given 96 and 48 h prior to benzo(a)pyrene, also inhibited zoxymethanol and then to the hypothetical intermediate methylazoxy- forestomach neoplasia in female A/J mice (17). In all of these studies, formaldehyde which is further converted to the methylating species, the organosulfur compounds appeared to inhibit the activation of the methyldiazonium hydroxide (24), in either the liver or colon. The carcinogen or to trap the activated carcinogenic species. The detailed inhibition of NDMA-induced hepatocarcinogenesis by disulfiram (25) mechanisms remain to be elucidated. may also be interpreted on the basis that disulfiram is an inhibitor and The possibility that DAS may exert its anticarcinogenic action by inactivator of P450 2E1 (10, 26). Inhibition of 4-(Methylnitrosamino)-l-(3-pyridyl)-l-butanone induction of detoxification enzymes has also been investigated. Pre treatment of rats and mice with DAS has been shown to increase (1.3- Bioactivation and Lung Tumorigenesis by DAS and I) \SOâ€ž to 2.5-fold) glutathione S-transferase, glutathione peroxidase, and NNK is a potent tobacco carcinogen which is believed to be important glutathione reducÃaseactivities, as well as the levels of a, /j,, and -n in human cancer etiology, especially in the causation of oral cancer in class glutathione S-transferases (17, 30-32). However, the induction tobacco chewers and lung cancer in cigarette smokers (27). It was observed previously in our laboratory that p.o. administration of DAS of detoxification enzymes by organosulfur compounds is a rather slow markedly decreased the rate of NNK bioactivation in mouse lung and process and in many cases rather low in magnitude (17, 31-33). rat nasal mucosa microsomes (28, 29). The a-methylene oxidation Induction of detoxification enzymes may be an important factor of the pathway, which leads to the generation of a methylating agent and the chemopreventive action of organosulfur compounds only in certain keto aldehyde [4-oxo-l-(3-pyridyl)-l-butanone], was decreased by cases. 80% in mouse lung microsomes. The rate of the bioactivation of NNK Other garlic-related compounds or products such as 1-propenyl was decreased even more extensively in rat nasal mucosa microsomes, sulfide, ajoene, and garlic oil have been shown to inhibit tumor but only moderately in liver microsomes. This decrease in metabolic promotion by phorbol-myristate acetate on mouse skin (34). Inhibition activity appears not to be related to P450 2E1 inactivation, and the of lipoxygenase and ornithine decarboxylase are the possible mech mechanisms remain to be elucidated. However, this result suggested anisms of such an inhibition. that DAS would inhibit NNK-induced lung tumorigenesis. This in hibitory activity was demonstrated experimentally. A single dose of Inhibition of Carcinogen Activation and Carcinogenesis by NNK (2 mg/mouse, i.p.) given to female A/J mice, induced lung Isothiocyanates adenomas in almost all the animals after 16 weeks, with an average of 9 Â±1.3 tumors per mouse. When DAS was given to the mice p.o. at PEITC and benzyl isothiocyanate which occur as glucosinolates in a daily dose of 200 mg/kg for 3 days with the final dose given 2 h many cruciferous vegetables have been shown to inhibit carcinogen prior to NNK administration, the tumor incidence was reduced by esis in several animal models (35-37). These two isothiocyanates 60% and tumor multiplicity was decreased by 90% (29). A similar were shown to inhibit 7,12-dimethylbenz(a)anthracene-induced mam extent of inhibition was also produced with DASO2 at a dose of 100 mary tumorigenesis in rats and tumor formation in forestomach and mg/kg; at a dose of 20 mg/kg, the tumor multiplicity was inhibited by lung of ICR/Ha mice (36). Benzyl isothiocyanate administered shortly 38% but the tumor incidence was not affected.5 before carcinogen treatment inhibited yV-nitrosodicthylamine-induced 1983s

Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 1994 American Association for Cancer Research. ( VIIÂ«Ã•WOMI S l'-4>ll ANI) ( MlMOI'RI-VKNTION forcstomach tumors and benzo(a)pyrene-induced lung and forestom- 6-phenylhexyl isothiocyanate exhibited much lower KÂ¡values than ach tumors in A/3 mice (36). PEITC (11-16 nM versus 51-93 nM), suggesting that 6-phenylhexyl Mechanisms of Inhibition by Phenethyl Isothiocyanate. In isothiocyanate has a higher affinity for binding at the active site of the NNK-induced lung tumorigcnesis. PEITC is effective only when P450 involved in the bioactivation of NNK (40, 43). It appears that given prior to or during the NNK treatment period, suggesting that blocking P45()-dependent activation of NNK is the major mechanism PEITC inhibits the activation of NNK (35). In order to understand the for the inhibition of carcinogenesis, although other factors may also be mechanisms of such an inhibition, we have studied the effects of involved (42). PEITC and other isothiocyanates on the activation of NNK as well as With other isothiocyanates, an increase of phase II enzyme activi on phase I and phase II drug-metabolizing enzymes in rodents (38- ties and the tissue glutathione level (36, 44) can be an important 40). When added to incubations with A/ÃŒmouse lung microsomes, protective mechanism. Benzyl isothiocyanate has been shown to in PEITC is a competitive inhibitor (with K{of 50 nM) for the low Km (2 crease the activities of glutathione 5-transferase, NAD(P)H:quinone to 5 /XM) form of NNK activation enzyme. The identity of the oxidoreductase, and UDP-glucuronyl transferase (43, 45^48). Further enzyme(s) remains to be determined, although indirect evidence sug more, dietary benzyl isothiocyanate increased sulfhydryl levels and the level of glutathione 5-transferase subunit 2 (of the a class) (45, 47, gests the involvement of P450. In addition, PEITC caused an NADPH-independent irreversible inhibition of the enzyme activity, 48). Allyl isothiocyanate, a hydrolysis product of sinigrin, has also been shown to strongly induce glutathione 5-transferase activity and most likely due to the chemical inactivation of the enzyme(s) in the glutathione S-transferase subunit 2 level (49). The induction of volved. However, some of the liver xenobiotic metabolizing activities glutathione 5-transferase subunit 2 by allyl isothiocyanate was similar were less susceptible to the inhibition by PEITC. For example, the to the induction pattern in rats receiving a diet containing 30% NDMA demethylase activity was inhibited by PEITC exhibiting a brussels sprouts (49). The presence of an a-hydrogen is required for competitive inhibition (Kt = 1 /XM)and suicide inhibition at 5 JUM the inductive activity of isothiocyanates (50). PEITC; the benzphetamine and ethylmorphine demethylase activities were only slightly inhibited by 20 JIM PEITC (41). Possible Application of Other P450 Inhibitors When administered to mice or rats, PEITC produced a large de crease in the rate of NNK oxidation in microsomes. The lung enzyme Many compounds have been shown to inhibit P45()-dependent activation of carcinogens and they are referred to as "blocking agents" activities were decreased to a greater extent than that of the liver and the effect lasted for at least 24 h at which time the liver enzyme by Wattenberg (36). However, in light of the discussions in the activities had recovered to or slightly above the control values. Further previous sections, only those with selective inhibitory activities to examination of the liver microsomes indicated that the NDMA de ward certain known chemical carcinogens may have potential for methylase activity (due to P450 2E1) was dramatically decreased, practical application. most likely due to a suicide inactivation mechanism. The EROD and Flavonoids, many of which are widely distributed in fruits, vege tables, and nuts, have been shown to modulate P45()-mediated me erythromycin demethylase activities, due mainly to P450s 1A2 and 3A, respectively, were also decreased and recovered in 24 h. In tabolism of carcinogens (2, 51, 52). Early studies have suggested that contrast, the PROD activity and P450 2B level were markedly in flavonoids with hydroxyl groups, such as quercetin, naringenin, and creased (39). The lung PROD and EROD activities were not signifi fisetin are inhibitors; whereas those with methoxy groups or without cantly affected. The hepatic NAD(P)H:quinonc oxidoreductase activ hydroxyl groups, such as tangeretin, nobiletin, and flavone are stim ity increased by 5-fold and the glutathione S-transferase activity ulators of P450-dependent reactions (2). However, recent results sug increased 1.5-fold, but the sulfotransferase activity decreased by 32â€” gest that the effects of flavonoids vary with the P450 forms involved. 48%; these activities were not significantly changed in the lung (39). For example, flavone and tangeretin are both potent inhibitors with Chronic feeding of PEITC (1 or 3 jumol/g diet) for 4 weeks caused 50% lethal concentration values lower than 7 /AMfor human liver similar effects on the aforementioned xenobiotic-metabolizing activ microsomal EROD activity, presumably due to the inhibition of P450 1A2. However, tangeretin is a stimulator of the erythromycin demeth ities, except that the NDMA demethylase activity and P450 2E1 were ylase activity, presumably due to the stimulation of P450 3A4.S Some increased (40). These results suggest that inhibition of P450-dependent activation, of these compounds may have practical application in the prevention rather than the induction of phase II enzymes, is mainly responsible of cancer; for example, in areas where aflatoxin B, is a major for the chemopreventive effect of PEITC against NNK-induced lung causative factor of hepatocellular carcinoma. It has been reported that tumorigcnesis. PEITC, when given to rats or when added to micro- aflatoxin B, is predominantly activated by human P450 3A4 (1). somal incubations, also decreased the metabolic activation of NMBzA However, recent results suggest that human P450 l A2 may be the low in esophageal microsomes much more extensively than in liver mi Km enzyme for the activation of this carcinogen. In either case, the crosomes.5 It appears that inhibition of carcinogen activation is also inhibition of aflatoxin B, activation by quercetin and naringenin is the mechanism by which PEITC inhibits NMBzA-induced esophageal expected. If the important role of P450 1A2 in aflatoxin B, activation carcinogenesis (37). in humans can be further substantiated, the possible application of Inhibitory Activities of Other Isothiocyanates. A structure-ac tangeretin and flavone for cancer chemoprevention may be explored. tivity relationship in the inhibitory potency of different aromatic These inhibitors may also be useful in blocking the activation of isothiocyanates has been observed. As the alkyl chain length of the heterocyclic amines which are known to be present in cooked foods isothiocyanate increases, the extent of the inhibition on NNK-induced and are activated by P450 1A2 (6, 53). tumor formation. DNA adduci formation, oxidation of NNK, and Opportunities and Problems Associated with Inhibition of erythromycin (V-demethylase activity is increased (38, 42, 43). The Hepatic P450 order of potency is 6-phenylhexyl isothiocyanate > 4-phenylbutyl isothiocyanate > 3-phenylpropyl isothiocyanate > PEITC > benzyl Inhibition of hepatic P450 by dietary chemicals offers the oppor isothiocyanate. An increased alkyl chain length may favor binding of tunity to block the activation of toxicants or carcinogens in the liver the isothiocyanates to the active sites of the P450 enzymes. Both and thereby reduce hepatotoxicity and hepatocarcinogenesis. The PEITC and 6-phenylhexyl isothiocyanate (a synthetic isothiocyanate) inhibition of NDMA-, carbon tetrachloride-, and APAP-induced hep decreased the oxidation of NNK in a competitive manner; however, atotoxicity by DAS has been demonstrated (18, 54). Recent results lW4s

Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 1994 American Association for Cancer Research. CYTOCHROMES P-450 AND CHEMOPREVENTION indicate that APAP-induced hepatotoxicity in rats and mice was and Nebert. D. W. 0- The P450 superfamily: update on new sequences, gene mapping, accession numbers, early trivial names of enzymes, and nomenclature. prevented when DASO, (50 mg/kg) was given concomitantly, or l h DNA Cell Biol., 12: 1-51, 1993. (rats), or 20 min (mice) after a toxic dose of APAP. DASO, inhibited 6. Guengerich, F. P. Characterization of human cytochrome P450 en/ymes. FASEB J.. the rate of yV-acetyl-p-benzoquinoneimine-glutathione formation by 6: 745-748, 1992. 7. Yang, C. S., Brady, J. F., and Hong. J-Y. Dietary effects on cytochromes P-450. 75%, primarily due to the inhibition of P450 2E1 and partly to the inhibition of P450 3A4 and P450 1A2 (54).5 Furthermore, a single xenobiotics metabolism, and toxicity. FASEB J.. ft: 737-744. 1992. 8. Yang, C. 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Chung S. Yang, Theresa J. Smith and Jun-Yan Hong

Cancer Res 1994;54:1982s-1986s.

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