Effect of dehydroepiandrosterone (DHEA) on the metabolism of 7,12-dimethylbenz[a]anthracene (DMBA) in rats

Abstract

The influence of dehydroepiandrosterone (DHEA), an adrenal steroid, on the biotransformation of the carcinogen 7,12-dimethylbenz[a]anthracene (DMBA) in rats has been investigated. Male Sprague-Dawley rats (2-3 months old) were fed DHEA for 14 days at a dietary level of 0.8%. There was an increase in liver weights with increases per whole liver, in total protein, microsomal and cytosolic protein and cytochrome P-450, and cytosolic glutathione transferase activity in DHEA fed rats. DNA content of the liver, however, remained constant. Forty-eight hours after a single i.p. dose of [3H]DMBA (133 mumol/kg body weight, 102 muCi/rat) binding of DMBA derived metabolites to DNA decreased significantly both per unit of DNA (605 versus 194 pmol/mg DNA) as well as per whole liver DNA (25.4 versus 8.5 nmol) in DHEA fed rats. However, a significantly higher amount of DMBA-derived metabolites were bound to total hepatic protein (455 versus 288 nmol) in the steroid fed rats. Microsome mediated binding of DMBA to DNA was 3-fold higher in DHEA fed rats. Excretion of DMBA-derived metabolites in urine was 2-fold higher in DHEA fed rats. The results of this study demonstrate that DHEA inhibits binding of DMBA to hepatic DNA in vivo in spite of the increased metabolic activation of the carcinogen perhaps due to increased detoxification and competitive binding of its active species to proteins.