The proximate carcinogen trans-3,4-dihydroxy-3,4-dihydro-dibenz[c,h]acridine is oxidized stereoselectively and regioselectively by cytochrome 1Al, epoxide hydrolase and hepatic microsomes from 3-methylcholanthrene-treated rats

Metabolism of the proximate carcinogen trans-3,4-dihydroxy-3,4dihydrodibenz [c,h]acridine has been examined with rat liver enzymes. The dihydrodiol is metabolized at a rate of 2.4 nmol/nmol of cytochrome P450 1A1/min with micr osomes from 3-methylcholanthrene-treated rats, a rate more than 10-fold hig her than that observed with microsomes from control or phenobarbital-treate d rats. Major metabolises consisted of a diastereomeric pair of bis-dihydro diols (68-83%), where the new dihydrodiol group has been introduced at the 8,9-position, tetraols derived From bay region 3,4-diol-1,2-epoxides (15-23 %), and a small amount of a phenolic dihydrodiol(s) where the new hydroxy g roup is at the 8,9-position of the substrate. A highly purified monooxygena se system reconstituted with cytochrome P450 1A1 and epoxide hydrolase (17 nmol of metabolites/nmol of cytochrome P450 1A1/min) gave a metabolite prof ile very similar to that observed with liver microsomes from 3-methylcholan threne-treated rats. Study of the stereoselectivity of these microsomes est ablished that the (+)-(3S,4S)-dihydrodiol gave mainly the diol epoxide-1 di astereomer, in which the benzylic 4-hydroxyl group and epoxide oxygen are c is. The (-)-(3R,4R)-dihydrodiol gave mainly diol epoxide-2 where these same groups are trans. The major enantiomers of the diastereomeric bis-dihydrod iols are shown to have the same absolute configuration at the 8,9-position. Correlations of circular dichroism spectra suggest this configuration to b e (8R,9R). The (8R,9S)-oxide may be their common precursor. (C) 1999 Elsevi er Science Ireland Ltd. All rights reserved.