The metabolism of the carcinogen 7-methylbenz[c]acridine by hepatocytes isolated from untreated and induced rats

Abstract

1. The metabolic fate of the carcinogenic aza-aromatic hydrocarbon 7-methyl[^7-14C]benz[c]acridine (¹⁴C-7MBAC) was studied in hepatocytes freshly isolated from untreated, phenobarbital-pretreated and 3-methylcholanthrene-pretreated rats.

2. ¹⁴C-7MBAC (4-200 µM) was metabolized in a concentration-dependent manner; Michaelis-Menten kinetics were not followed.

3. Using 100 µM ¹⁴C-7MBAC, the bulk of the ethyl acetate-extractable metabolites were found in the incubation medium; about 50% of the total metabolites were not extractable into ethyl acetate.

4. The nature of the water-soluble metabolites was examined by enzyme hydrolysis of glucuronides and sulphates, and by glutathione-depletion experiments. Organo-extractable metabolites were examined by reverse-phase h.p.l.c. and quantified by co-chromatography with standards.

5. Pretreatment of the rats with mixed-function oxidase inducers, phenobarbital and 3-methylcholanthrene resulted in 2.85- and 5.70-fold increases, respectively, in total metabolism of ¹⁴C-7MBAC.

6. Major metabolites for all three hepatocyte preparations co-chromatographed with 7-hydroxymethylbenz[c]acridine, trans-5,6-dihydro-5,6-dihydroxy-7-methylbenz[c]-acridine and trans-8,9-dihydro-8,9-dihydroxy-7-methylbenz[c]acridine.