3-Methylcholanthrene carcinogenic activity

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. 

Methylcholanthrene (3-MC) is a potent carcinogen, intermediate in activity between DMBA and BP (27,77). It was first prepared in 1925 by Wieland from desoxycholic acid (89). Biological studies have tentatively identified the 9,10-dihydrodiol (24a) and/or its 1- or 2-hydroxy derivatives (24b and 24c) and the corresponding diol and triol epoxides (25 -c) as the proximate and ultimate carcinogenic forms, respectively, of 3-MC (90-93). 

Benzoflavene also exerts similar effects, also blocking the carcinogenic effect of 3-methylcholanthrene and 7,12-dimethylbenzo[a]anthracene. In-dol derivatives also block the activity of BaP-hydrolase in addition to the inhibition of 7,12-dimethylbenzo[a]anthracene. 

Studies of the effects of typical inducers of mixed-function oxidase activity on DMN demethylation have also produced contradictory results. One group found that 3-methylcholanthrene and other PAH inhibited rat hepatic DMN demethylase activity (and DMN carcinogenicity) (474, 476), while others observed an increase in activity (136, 331, 374). Similar results were obtained in studies with Aroclor 1254, which was shown by one group to induce DMN demethylase activity in mouse liver (90), while other investigators found no change in activity (14). Contradictory results were also observed with phenobarbital (10, 13, 331, 374). These contradictions appear to have been at least partially resolved by the discovery of two hepatic forms of DMN demethylase. These two forms of DMN demethylase appear to respond differently to pretreatment with typical enzyme inducers one form is induced and the other repressed (11). The two different forms catalyze DMN demethylation at low substrate concentrations (0-4 mM)... 

Feeder-layer experiments depend on the ability of a chemical activated by an irradiated feeder layer of metabolizing cells to induce SCEs in exponentially dividing tester cells. Syrian hamster secondary embryo cultures that have been shown to metabolize various carcinogenic polycyclic aromatic hydrocarbonsare used as the feeder layer, and Chinese hamster V79 cells are the tester cells. The irradiated embryo culture cells are mixed with the V79 cells before being plated in petri dishes. Chemicals are added 24 hr later with BrdUrd, and the cells are fixed after an additional 24 hr. Positive results are obtained with benzo[a]pyrene, 3-methylcholanthrene, and dimethylben-zanthracene, none of which induces SCEs in the absence of the feeder layer. 

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