Influence of dietary thiamin on phenobarbital induction of rat hepatic enzymes responsible for metabolizing drugs and carcinogens

Abstract

Male and female Sprague-Dawley rats were fed synthetic diets deficient in or supplemented with thiamin for 2 or 3 weeks. One group of rats receiving the thiamin-supplemented diet was pair-fed the amount consumed by rats fed the thiamin-deficient diet. One-half of each group was administered phenobarbital sodium for four consecutive days prior to decapitation. Rats fed the thiamin-deficient diet had higher NADPH cytochrome c reductase, aniline hydroxylase, and ethylmorphine N-demethylase activities than those fed high levels of thiamin. In addition, these animals generally responded more vigorously to induction by phenobarbital in their synthesis of microsomal protein, and increased activities of NADPH cytochrome c reductase, aniline hydroxylase, and ethylmorphine N-demethylase. Cytochrome P-450 concentration was higher in the microsomes from thiamin-deficient rats and was induced to a greater degree by phenobarbital than in microsomes from rats fed thiamin-supplemented diets ad libitum. Phenobarbital-enhanced metabolism of N-nitrosodimethylamine (DMN) by liver 9,000 g supernatant as evidenced by approximately two-fold increases in formaldehyde formed per gram liver. This increase in DMN metabolism in male rats is due at least in part to the increased concentration of microsomal protein, since metabolism per milligram microsomal protein was not increased. The fact that DMN metabolism per unit of microsomal cytochrome P-450 in phenobarbital-treated animals is decreased to about one-half of that in controls indicates that DMN is either metabolized by a non-cytochrome P-450-dependent system or that it is metabolized by a form of P-450 not induced by phenobarbital. A sex difference was evident in these experiments, females generally being more sensitive to the influence of varying levels of dietary thiamin. Also female rats but not males fed high-thiamin diets responded to phenobarbital with increased DMN metabolism per milligram microsomal protein.