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The Metabolism of the Carcinogen Dibenz[a,j]acridine in Isolated Rat Hepatocytes and in Vivo in Rats

The Metabolism of the Carcinogen Dibenz[a,j]acridine in Isolated Rat Hepatocytes and in Vivo in Rats

H K Robinson, C C Duke, G M Holder, A J Ryan

Xenobiotica. 1990 May;20(5):457-70.

PMID: 2349805

Abstract:

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP224420	Dibenz(a,j)acridine		224-42-0	Price

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