The proximate carcinogen trans-3,4-dihydroxy-3,4-dihydro-dibenz[c,h]acridine is oxidized stereoselectively and regioselectively by cytochrome 1A1, epoxide hydrolase and hepatic microsomes from 3-methylcholanthrene-treated rats.
Metabolism of the proximate carcinogen trans-3,4-dihydroxy-3,4-dihydrodibenz[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 microsomes from 3-methylcholanthrene-treated rats, a rate more than 10-fold higher than that observed with microsomes from control or phenobarbital-treated rats. Major metabolises consisted of a diastereomeric pair of bis-dihydrodiols (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 group is at the 8,9-position of the substrate. A highly purified monooxygenase system reconstituted with cytochrome P450 1A1 and epoxide hydrolase (17 nmol of metabolites/nmol of cytochrome P450 1A1/min) gave a metabolite profile very similar to that observed with liver microsomes from 3-methylcholanthrene-treated rats. Study of the stereoselectivity of these microsomes established that the (+)-(3S,4S)-dihydrodiol gave mainly the diol epoxide-1 diastereomer, in which the benzylic 4-hydroxyl group and epoxide oxygen are cis. The (-)-(3R,4R)-dihydrodiol gave mainly diol epoxide-2 where these same groups are trans. The major enantiomers of the diastereomeric bis-dihydrodiols are shown to have the same absolute configuration at the 8,9-position. Correlations of circular dichroism spectra suggest this configuration to be (8R,9R). The (8R,9S)-oxide may be their common precursor.
Adams
J D
JD
University of Southern California, School of Pharmacy, Los Angeles 90089-9121, USA. jadams@hsc.usc.edu
Sayer
J M
JM
Chadha
A
A
Shirai
N
N
Lehr
R E
RE
Kumar
S
S
Jerina
D M
DM
D000166:Acridines / Q000378:metabolism* / Q000493:pharmacokinetics / Q000633:toxicity; D000818:Animals; D001551:Benz(a)Anthracenes / Q000378:metabolism* / Q000493:pharmacokinetics / Q000633:toxicity; D001711:Biotransformation; D002273:Carcinogens / Q000378:metabolism* / Q000493:pharmacokinetics / Q000633:toxicity; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism*; D004851:Epoxide Hydrolases / Q000378:metabolism*; D008297:Male; D008748:Methylcholanthrene / Q000633:toxicity; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism*; D010084:Oxidation-Reduction; D051381:Rats; D020318:Rats, Long-Evans; D013237:Stereoisomerism; D013379:Substrate Specificity
D000166:Acridines; D001551:Benz(a)Anthracenes; D002273:Carcinogens; C022289:dibenzacridine; C018912:dibenzoanthracene-3,4-dihydrodiol; D008748:Methylcholanthrene; D019363:Cytochrome P-450 CYP1A1; D004851:Epoxide Hydrolases