Metabolic pathways of 7,12-dimethylbenz[a]anthracene in hepatic microsomes.

Yang, Shen K.; Dower, William V.

doi:10.1073/pnas.72.7.2601

Cited by 29 publications

(12 citation statements)

References 40 publications

(76 reference statements)

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“…Studies on the metabolic activation pathways of DMBA by P450s have been conducted with liver microsomes from rodents and humans [14,15,19,25,26] and cDNA-expressed [27] and purified animal P450s in reconstituted systems [28]. These studies have been directed at understanding the roles of specific forms of P450s that are responsible for the metabolism of DMBA.…”

Section: Shou Et Almentioning

confidence: 99%

Specificity of cDNA-expressed human and rodent cytochrome P450s in the oxidative metabolism of the potent carcinogen 7,12-dimethylbenz[a]anthracene

et al. 1996

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7,12-Dimethylbenz[a]anthracene (DMBA), a potent carcinogen, requires metabolic activation by cytochrome P450s (P450s) to electrophilic metabolites that result in DNA modification, mutagenicity, and carcinogenicity. In this study, we used eight human forms, four rodent forms, and one rabbit form of P450 expressed from recombinant vaccinia or baculovirus vectors to define their specificity for metabolizing DMBA. Of the eight human P450s, 1A1 was the most active (specific activity = 14.7 nmol/min/nmol of P450) in total metabolism of DMBA and showed approximately 6- to 33-fold more activity than other P450s, 2B6, 2C9, and 1A2 were also capable of metabolizing DMBA (2.0-2.5 nmol/min/nmol of P450), whereas 2C8, 2E1, 3A4, and 3A5 exhibited relatively low activities. Among animal P450s, mouse 1A1 exhibited activity similar to that of human 1A1 and had 5.0- to 37-fold more activity than other rodent and rabbit P450s. In regard to enzyme regioselectivity, most human and rodent P450s predominantly formed the 8,9-diol, but human 2B6 and rat 2B1 preferentially formed the 5,6-diol. In the production of monohydroxymethyl metabolites, all the enzymes yielded more 7-hydroxymethyl-12-methylbenz[a]anthracene (7HOM12MBA) than 12-hydroxymethyl-7-methylbenz[a]anthracene (7M12HOMBA), except for human 1A1, which presented the reverse selectivity. Human liver microsomes from 10 organ donors were shown to metabolize DMBA and in most circumstances generated the metabolic profile DMBA trans-8,9-dihydrodiol > 7HOM12MBA > or = DMBA trans-5,6-dihydrodiol > or = 7,12-dihydroxymethylbenz[a]anthracene > 7M12HOMBA > DMBA trans-3,4-dihydrodiol. Thus, the combined activity of hepatic microsomal 2C9, 1A2, and 2B6 may contribute to the metabolic activation and the metabolism of DMBA in normal human liver.

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Section: Shou Et Almentioning

confidence: 99%

Specificity of cDNA-expressed human and rodent cytochrome P450s in the oxidative metabolism of the potent carcinogen 7,12-dimethylbenz[a]anthracene

et al. 1996

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“…It is clear that differences in the identities of the metabolites could exist which would require more sensitive techniques for their detection. High-pressure liquid chromatography would be useful in testing this possibility (Soedigdo, Angus and Flesher, 1975;Yang and Dower, 1975). Almost identical results were obtained using liver cell fractions from DMBAinjected partially hepatectomized animals.…”

mentioning

confidence: 67%

Metabolism of 7,12,-dimethylbenz(a)anthracene by normal and regenerating rat livers

Tomsak¹,

Cook²

1977

Br J Cancer

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Summary.-The in vitro metabolisms of [14C]7,12 -dimethylbenz(a)anthracene (DMBA) by post-mitochondrial supernates and microsomes from intact and regenerating rat livers were compared. Both cell fractions from regenerating livers at 48, 72, and 96 h after partial hepatectomy metabolized less [14C]DMBA than similar fractions from intact livers. Prior in vivo treatment with DMBA enhanced metabolism by the cell fractions from both groups, but specific activities of cell fractions from regenerating livers were always about 60% or less of those from intact livers. Thinlayer chromatographic analysis of metabolites formed in incubations using either cell fraction failed to reveal distinct differences between ether-soluble or water-soluble products of similar fractions from intact and regenerating livers. However, highly reproducible differences were found between chromatograms of water-soluble metabolites formed by microsomes and post-mitochondrial supernates in both intact and regenerating livers. Extrapolations from these studies indicate large differences in the metabolic capacity of intact and regenerating livers when expressed on a whole-liver basis, but it is suggested that there may be additional factors contributing to the increased retention of DMBA by regenerating livers.ACTIVELY dividing cells are more sensitive to chemical carcinogenesis than are non-dividing cells (Warwick, 1971;Weisburger and Williams, 1975). For example, regenerating rodent liver is more susceptible than intact liver to tumour induction by 7,12-dimethylbenz-(a)anthracene (DMBA) (Pound, 1968;Marquardt, Sternberg and Philips, 1970) and other chemical carcinogens (Chernozemski and Warwick, 1970;Craddock, 1973), but the reasons for this vulnerability are not known with certainty. In a comparison of [3H]DMBA uptake and persistence in intact and regenerating liver, we found that unmetabolized DMBA persisted at high levels in nuclei and other fractions from regenerating liver, but rapidly disappeared from intact liver; preliminary experiments demonstrated that hepatic microsomes from DMBAtreated partially hepatectomized animals metabolized less [14C]DMBA in vitro than did microsomes from DMBA-treated intact animals (Tomsak and Cook, 1975).We now report a more detailed quantitative comparison of DMBA metabolism, using microsomes and post-mitochondrial supernates prepared from intact and regenerating livers, and also report comparative analyses of DMBA metabolites, using thin-layer chromatography as a screening technique.

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“…Recently, high pressure liquid chromatography (h.p.1.c.) has enabled quantitative analysis of the in vitro metabolites of DMBA (Yang & Dower, 1975). The results show 7-methyl-and 12-methyl-hydroxylation to be significant routes of metabolism of practically equal importance in control and 3-methylcholanthrene-induced rat liver microsomes.…”

Section: Oxidation Of Sterically Non-equivalent Methyl Groupsmentioning

confidence: 87%