Variations dependent on Age and Diet in the Metabolism of 7,12-Dimethylbenz[a]-anthracene by Rat Liver Homogenates

Abstract

7,12-DIMETHYLBENZ[A]ANTHRACENE (DMBA) causes severe adrenocortical necrosis when administered intragastrically to 50 day old rats¹, but it has no effect on the adrenal glands of 25 day old animals². The activity of the hydrocarbon seems to depend on the formation of an active metabolite, probably 7-hydroxymethyl-12-methylbenz[a]anthracene (7-OHM-12-MBA)^3,4; the isomeric 12-hydroxymethyl-7-methylbenz[a]anthracene (12-OHM-7-MBA) is a metabolic product of DMBA but has no effect on the adrenal³. Damage to the adrenal can be prevented by pretreating animals with compounds that enhance hepatic detoxicating enzymes^5,6, apparently by increasing the yields of inactive ring-hydroxylated products, such as 8,9-dihydro-8,9-dihydroxy-7,12-dimethylbenz[a]anthracene, at the expense of those hydroxylated on the methyl groups and also by inactivating 7-OHM-12-MBA itself by ring hydroxylation, to yield products such as 8,9-dihydro-8,9-dihydroxy-7-hydroxymethyl-12-methylbenz[a]anthracene⁷. Treatments which reduce hepatic detoxicating enzymes also prevent DMBA-induced adrenal necrosis⁸, probably by reducing the overall metabolism of the hydrocarbon. It seemed possible that the differing susceptibilities to DMBA-induced adrenal necrosis of the 25 and 50 day old rats developed because animals of the two age groups have different activities of hepatic enzymes, and so we have investigated the in vitro metabolism of DMBA by liver homogenates prepared from rats of different ages.