PT  - JOURNAL ARTICLE
AU  - M. NORDQVIST
AU  - D. R. THAKKER
AU  - W. LEVIN
AU  - H. YAGI
AU  - D. E. RYAN
AU  - P. E. THOMAS
AU  - A. H. CONNEY
AU  - D. M. JERINA
TI  - The Highly Tumorigenic 3,4-Dihydrodiol Is a Principal Metabolite Formed from Dibenzo[a,h]anthracene by Liver Enzymes
DP  - 1979 Sep 01
TA  - Molecular Pharmacology
PG  - 643--655
VI  - 16
IP  - 2
4099  - http://molpharm.aspetjournals.org/content/16/2/643.short
4100  - http://molpharm.aspetjournals.org/content/16/2/643.full
SO  - Mol Pharmacol1979 Sep 01; 16
AB  - Pretreatment of rats with 3-methylcholanthrene or Aroclor-1254 caused a 2- to 3-fold enhancement in the rate of metabolism of [14C]-dibenzo[a,h]anthracene (DBA) by liver microsomes and altered the relative amounts of some of the metabolites formed compared to metabolism by microsomes from untreated rats. These changes consisted mainly of a decrease in phenols and an increase in unidentified minor metabolites. Pretreatment of rats with phenobarbital caused less marked changes in the profile of metabolites formed from DBA, and the rate of metabolism of DBA was significantly reduced per nmol of cytochrome P-450 compared to microsomes from untreated rats. Under all incubation conditions, DBA 3,4-dihydrodiol was the major dihydrodiol metabolite which accounted for 24-28% of the total metabolites. Less than half this amount of the 1,2-dihydrodiol was formed, and only trace amounts of the K-region 5,6-dihydrodiol could be detected. Two major phenolic metabolite fractions were detected. After 3-methylcholanthrene- or Aroclor-pretreatment, metabolites more polar than the dihydrodiols were also formed. In the absence of epoxide hydrase, DBA was converted primarily into phenols by a purified and reconstituted cytochrome P-448 monooxygenase system. Addition of highly purified epoxide hydrase resulted in the formation of DBA 1,2- and 3,4-dihydrodiols as well as more polar metabolites with a concomitant decrease in the amounts of phenolic metabolites. The predominance of DBA 3,4-dihydrodiol as a metabolite on incubation of DBA either with rat liver microsomes or with the highly purified, reconstituted monooxygenase system in the presence of epoxide hydrase is of considerable importance since this is the most potent carcinogenic metabolite of DBA presently known. The 3,4-dihydrodiol formed from DBA by liver microsomes from 3-methylcholanthrene-treated rats was found to be 60% optically pure. Evidence is presented which indicates that bay region diol epoxides are formed from racemic DBA 3,4-dihydrodiol. ACKNOWLEDGMENTS We wish to thank Mrs. Janet Deyhle and Mrs. Rosemary DePue for their help in the preparation of this manuscript. One of us (M.N.) acknowledges a Fogarty International Fellowship and a scholarship from the Fulbright Commission for International Exchange of Scholars.