5-Methylchrysene metabolites

Methods for the synthesis of the biologically active dihydrodiol and diol epoxide metabolites of both carcinogenic and noncarcinogenic polycyclic aromatic hydrocarbons are reviewed. Four general synthetic routes to the trans-dihydrodiol precursors of the bay region anti and syn diol epoxide derivatives have been developed. Syntheses of the oxidized metabolites of the following hydrocarbons via these methods are described benzo(a)pyrene, benz(a)anthracene, benzo-(e)pyrene, dibenz(a,h)anthracene, triphenylene, phen-anthrene, anthracene, chrysene, benzo(c)phenanthrene, dibenzo(a,i)pyrene, dibenzo(a,h)pyrene, 7-methyl-benz(a)anthracene, 7,12-dimethylbenz(a)anthracene, 3-methylcholanthrene, 5-methylchrysene, fluoranthene, benzo(b)fluoranthene, benzo(j)fluoranthene, benzo(k)-fluoranthene, and dibenzo(a,e)fluoranthene. 

In contrast, the fluorine atom at the peri-position of 12F-5-methylchrysene influences dihydrodiol formation in the adjacent angular ring. Whereas the ratio of 5-MeC-7,8-diol to 5-MeC-l,2-diol in mouse epidermis was 1 1, 2 hr after topical application of [%] 5-MeC, the ratio of 12F-5-methylchrysene-7,8-diol to 12F-5-methylchrysene-1,2-diol was 68 1. In contrast to 5-MeC, the metabolites formed from 12F-5-methylchrysene in mouse skin resulted almost exclusively from oxidation at the 7,8-bond (57). Thus, metabolic switching to the less tumorigenic 7,8-dihydrodiol appears to be the basis for the lower tumorigenicity of 12F-5-methylchrysene compared to 5-MeC. 

In studies on the metabolic activation of 5-MeC (Fig. 9), in vitro metabolism was coupled with mutagenicity and carcinogenicity assays. This work illustrates some techniques which may be used to elucidate structure and determine active metabolites. The metabolic activation of 5-MeC was of interest because of its high carcinogenicity and mutagenicity compared with the other methylchrysene isomers (183). In addition, 5-MeC has two dissimilar bay regions available for formation of bay region dihydrodiol epoxides. 

Fig, 10, High-pressure liquid-chromatographic trace of metabolites formed from 5-methylchrysene (5-MeC) by rat liver 9000 g supernatant. For identification of peaks A-I, see text. 

Fig. 11. HPLC traces of metabolites formed from 1- (A), 3- (B), and 7-fluoro-5-methylchrysene (7-F-5-MeC) (C) after incubation with rat liver 9000 g supernatant. 

Dimethylchrysene, its 1,2-dihydroxy and 1-hydroxy metabolites, and 1-hydroxy-5-(hydroxymethyl)-6-methylchrysene were resolved on a C g column (A = 254 run) using a complex 30/70-> 100/0 methanol/water gradient [165]. Similarly, dibenz[aj]anthracene (DBA) and thrm metabolites (5,6-dihydroxy-, 3,4-dihydroxy- and 1,2,3,4-tetrahydroxy-DBA) were resolved on a C g column (A = 254 nm) using a complex 60-min 50/50 — 100/0 methanol/water gradient [166]. 

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