Metabolism of Hydroxyalkyl Derivatives of 3-Hethylcholanthrene by Liver Microsomes.

摘要

3-Methylcholanthrene (3MC) is a potent carcinogen and requires metabolism by mammalian drug-metabolizing enzyme systems to exert its mutagenic and/or carcinogenic activities. 1-Hydroxy-3MC (1-OH-3MC), 2-hydroxy-3MC (2-OH-3MC), and 3-hydroxymethylcholanthrene (3-OHMC) are the major initial metabolites of 3MC. 1-OH-3MC and 2-OH-3MC are further metabolized to form 3MC-1-one, 3MC-2-one, 3MC trans-1,2-diol, and 3MC cis-1,2-diol. 2-OH-3MC and 3MC-2-one are potent carcinogens. Hence, the major ultimate carcinogens are believed to be derived from further metabolism of 2-OH-3MC, 3MC-2-one, and/or 3-OHMC. The objectives of this investigation arc: (1) to characterize the products and to determine the relative amounts formed by metabolism of 1-OH-3MC, 2-OH-3MC, 3-OHMC, 3MC-l-one, 3MC-2-one, 3MC trans-1,2-diol, and 3MC cis-1,2-diol (3MC hydroxylalkyl derivatives), by liver microsomes from untreated and P-450 enzyme inducer-treated rats, and (2) to compare the metabolism of a racemic 3H-labeled 1-0H-3MC by rat and human liver microsomes. The results will significantly contribute to the eventual understanding of the metabolic activation pathways of 3MC. 3MC hydroxylalkyl derivatives were synthesized for metabolism studies. Absolute configuration of enantiomeric 1-OH-3MC 2-OH-3MC, 3MC cis- and 3MC trans-1,2-diols were established by the exciton chirality method. Relative amounts of 3MC alcohols formed in 3MC metabolism by liver microsomes from untreated, 3MC- and PB-treated rats were 2-OH-3MC > 3-OHMC > 1-OH-3MC. The 1(S)-OH-3MC (53-73%) and 2(S)-OH-3MC (86-98%) were found to be the major enantiomers. By using racemic 1-OH-3MC and 2-OH-3MC, respectively, as substrates, liver microsomes from either PB- or 3MC-treated rats preferentially metabolized the 15-onantiomer and the 2R-enantiomer. Metabolites formed in the metabolism of each 3MC hydroxylalkyl derivative were separated by a combination of reversed-phase and normal-phase high performance liquid chromatography (HPLC).