Regio- and stereo-selective metabolism of 4-methylbenz[a]anthracene by the fungus Cunninghamella elegans

Publisher Website
Google Scholar
Abstract
Metabolism of 4-methylbenz[a]anthracene [a carcinogen] by the fungus C. elegans was studied. C. elegans metabolized 4-methylbenz[a]anthracene primarily at the methyl group, followed by further metabolism at the 8,9- and 10,11-positions to form trans-8,9-dihydro-8,9-dihydroxy-4-hydroxymethylbenz[a]anthracene and trans-10,11-dihydro-10,11-dihydroxy-4-hydroxymethylbenz[a]anthracene. There was no detectable trans-dihydrodiol formed at the methyl-substituted double bond (3,4-positions) or at the K region (5,6-positions). The metabolites were isolated by reversed-phase high-pressure liquid chromatography and characterized by the application of UV-visible-absorption-, 1-NMR- and mass-spectral techniques. The 4-hydroxymethylbenz[a]anthracene trans-8,9- and -10,11-dihydrodiols were optically active. Comparison of the CD [circular dichroism] spectra of the trans-dihydrodiols formed from 4-methylbenz[a]anthracene by C. elegans with those of the corresponding benz[a]anthracene trans-dihydrodiols formed by rat liver microsomal fraction indicated that the major enantiomers of the 4-hydroyxmethylbenz[a]anthracene trans-8,9-dihydrodiol and trans-10,11-dihydrodiol formed by C. elegans have S,S absolute stereochemistries, which are opposite to those of the predominantly 8R,9R- and 10R,11R-dihydrodiols formed by the microsomal fraction. Incubation of C. elegans with 4-methylbenz[a]anthracene under 18O2 and subsequent mass-spectral analysis of the metbolites indicated that hydroxylation of the methyl group and the formation of trans-dihydrodiols are catalyzed by cytochrome P-450 monooxygenase and epoxide hydrolase enzyme systems. The fungal monooxygenase-epoxide hydrolase enzyme systems are evidently stereo- and regioselective in the metabolism of 4-methylbenz[a]anthracene.