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Modification of benzo(a)pyrene metabolism in hepatic microsomes from untreated and induced rats by imidazole derivatives which inhibit monooxygenase activity and enhance epoxide hydrolase activity.
Drug Metab Dispos. 1983 Jul-Aug; 11(4):350-4.DM

Abstract

We have determined how four simple imidazole derivatives, namely 4(5)-phenylimidazole, 1-phenylimidazole, benzimidazole, and naphthimidazole, affect positional metabolism of benzo(a)pyrene (BaP) by hepatic microsomes from untreated, phenobarbital (PB)-induced and 3-methylcholanthrene (3MC)-induced male Wistar rats, and epoxide hydrolase activity with styrene oxide and BaP 4,5-oxide as substrates. The imidazole derivatives were potent inhibitors of total BaP metabolism in microsomes from control and PB-induced rats (I50 approximately 10(-5) M) but did not affect the proportions of BaP metabolites formed. In microsomes from 3MC-induced rats, only naphthimidazole inhibited metabolism at a concentration of 5 X 10(-4) M, but all four imidazole derivatives increased the proportion of BaP 9,10-dihydrodiol formed. Addition of purified epoxide hydrolase enzyme to assays had the same effect on metabolite profile in 3MC-induced rats as addition of imidazole derivatives. The imidazole derivatives enhanced epoxide hydrolase activity with styrene oxide, but not with BaP 4,5-oxide as substrate. This study shows that the dominant effect of imidazole derivatives on BaP metabolism varies with rat pretreatment. In hepatic microsomes from control and PB-induced rats, overall inhibition of oxidative metabolism is the dominant effect, whereas in microsomes from 3MC-induced rats, the effect on epoxide hydrolase is dominant. This study also shows that epoxide hydrolase activity limits the rate of formation of BaP 9,10-dihydrodiol by hepatic microsomes from 3MC-induced rats, but not by hepatic microsomes from control or PB-induced rats.

Authors

No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

6137342

Citation

James, M O., and P J. Little. "Modification of Benzo(a)pyrene Metabolism in Hepatic Microsomes From Untreated and Induced Rats By Imidazole Derivatives Which Inhibit Monooxygenase Activity and Enhance Epoxide Hydrolase Activity." Drug Metabolism and Disposition: the Biological Fate of Chemicals, vol. 11, no. 4, 1983, pp. 350-4.
James MO, Little PJ. Modification of benzo(a)pyrene metabolism in hepatic microsomes from untreated and induced rats by imidazole derivatives which inhibit monooxygenase activity and enhance epoxide hydrolase activity. Drug Metab Dispos. 1983;11(4):350-4.
James, M. O., & Little, P. J. (1983). Modification of benzo(a)pyrene metabolism in hepatic microsomes from untreated and induced rats by imidazole derivatives which inhibit monooxygenase activity and enhance epoxide hydrolase activity. Drug Metabolism and Disposition: the Biological Fate of Chemicals, 11(4), 350-4.
James MO, Little PJ. Modification of Benzo(a)pyrene Metabolism in Hepatic Microsomes From Untreated and Induced Rats By Imidazole Derivatives Which Inhibit Monooxygenase Activity and Enhance Epoxide Hydrolase Activity. Drug Metab Dispos. 1983 Jul-Aug;11(4):350-4. PubMed PMID: 6137342.
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TY - JOUR T1 - Modification of benzo(a)pyrene metabolism in hepatic microsomes from untreated and induced rats by imidazole derivatives which inhibit monooxygenase activity and enhance epoxide hydrolase activity. AU - James,M O, AU - Little,P J, PY - 1983/7/1/pubmed PY - 1983/7/1/medline PY - 1983/7/1/entrez SP - 350 EP - 4 JF - Drug metabolism and disposition: the biological fate of chemicals JO - Drug Metab Dispos VL - 11 IS - 4 N2 - We have determined how four simple imidazole derivatives, namely 4(5)-phenylimidazole, 1-phenylimidazole, benzimidazole, and naphthimidazole, affect positional metabolism of benzo(a)pyrene (BaP) by hepatic microsomes from untreated, phenobarbital (PB)-induced and 3-methylcholanthrene (3MC)-induced male Wistar rats, and epoxide hydrolase activity with styrene oxide and BaP 4,5-oxide as substrates. The imidazole derivatives were potent inhibitors of total BaP metabolism in microsomes from control and PB-induced rats (I50 approximately 10(-5) M) but did not affect the proportions of BaP metabolites formed. In microsomes from 3MC-induced rats, only naphthimidazole inhibited metabolism at a concentration of 5 X 10(-4) M, but all four imidazole derivatives increased the proportion of BaP 9,10-dihydrodiol formed. Addition of purified epoxide hydrolase enzyme to assays had the same effect on metabolite profile in 3MC-induced rats as addition of imidazole derivatives. The imidazole derivatives enhanced epoxide hydrolase activity with styrene oxide, but not with BaP 4,5-oxide as substrate. This study shows that the dominant effect of imidazole derivatives on BaP metabolism varies with rat pretreatment. In hepatic microsomes from control and PB-induced rats, overall inhibition of oxidative metabolism is the dominant effect, whereas in microsomes from 3MC-induced rats, the effect on epoxide hydrolase is dominant. This study also shows that epoxide hydrolase activity limits the rate of formation of BaP 9,10-dihydrodiol by hepatic microsomes from 3MC-induced rats, but not by hepatic microsomes from control or PB-induced rats. SN - 0090-9556 UR - https://www.unboundmedicine.com/medline/citation/6137342/Modification_of_benzo_a_pyrene_metabolism_in_hepatic_microsomes_from_untreated_and_induced_rats_by_imidazole_derivatives_which_inhibit_monooxygenase_activity_and_enhance_epoxide_hydrolase_activity_ L2 - http://dmd.aspetjournals.org/cgi/pmidlookup?view=long&pmid=6137342 DB - PRIME DP - Unbound Medicine ER -