The metabolism of the carcinogen dibenz[a,j]acridine in isolated rat hepatocytes and in vivo in rats.
1. 3H-Dibenz[a,j]acridine (DBAJAC) metabolism occurred readily in vitro in incubations with hepatocytes from phenobarbital-pretreated, 3-methylcholanthrene-pretreated and untreated rats, with the formation of water-soluble conjugates and unconjugated metabolites. 2. For incubations of 3H-DBAJAC with hepatocytes the major organic solvent-soluble metabolites found with and without beta-glucuronidase/arylsulphatase hydrolysis were the phenols, 3-hydroxy-DBAJAC, and 4-hydroxy-DBAJAC, and the proposed proximate carcinogen, trans-3,4-dihydroxy-3,4-dihydro-DBAJAC. The latter comprised 34-66% of the total organic solvent-soluble metabolites. 3. In contrast to results previously reported for rat hepatic microsomes, the K-region 5,6-oxide, and its dihydrodiol were minor metabolites detected after hepatocyte incubations. 4. Faecal excretion accounted for the bulk of radioactivity after i.p. doses of 3H-DBAJAC (0.5 mg/kg), and i.v. doses (0.5 mg/kg) were rapidly excreted into the 6 h bile. The organic solvent-soluble fraction obtained after enzymic hydrolysis of bile (approximately 25% of excreted radioactivity) was subjected to h.p.l.c. It contained polar secondary oxidation products and virtually no 3,4-dihydrodiol. 5. Experiments conducted with greater hepatocyte densities (10(7) cells/ml) and longer incubation times showed increased extents of metabolism, DNA and protein binding of radioactivity which paralleled the extent of metabolism. Very considerable metabolism of the 3,4-dihydrodiol occurred by the end of the incubation period.
Robinson
H K
HK
Department of Pharmacy, University of Sydney, NSW, Australia.
Duke
C C
CC
Holder
G M
GM
Ryan
A J
AJ
D000166:Acridines / Q000378:metabolism* / Q000493:pharmacokinetics; D000818:Animals; D001192:Arylsulfatases / Q000378:metabolism; D002273:Carcinogens / Q000378:metabolism* / Q000493:pharmacokinetics; D004247:DNA / Q000378:metabolism; D005243:Feces / Q000032:analysis; D005966:Glucuronidase / Q000378:metabolism; D006868:Hydrolysis; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology; D010634:Phenobarbital / Q000494:pharmacology; D011485:Protein Binding; D051381:Rats; D011919:Rats, Inbred Strains; D013056:Spectrophotometry, Ultraviolet
D000166:Acridines; D002273:Carcinogens; C022289:dibenzacridine; D008748:Methylcholanthrene; D004247:DNA; D001192:Arylsulfatases; D005966:Glucuronidase; D010634:Phenobarbital