Role of neonatal androgen in the development of hepatic microsomal drug-metabolizing enzymes.
The development of several hepatic microsomal drug-metabolizing enzyme activities in rats was studied in relation to its androgen dependence during the neonatal period. Rats with their androgen deprived during the neonatal period (female rats and male rats castrated at birth) respond less to androgen treatment at adulthood for the metabolism of aminopyrine, ethylmorphine and hexobarbital as compared to rats exposed to neonatal androgen (male rats, male rats castrated at birth but neonatally treated with androgen and male rats castrated at the age of 20 days). This difference in the degree of hepatic responsiveness, however, varied with the substrates: ethylmorphine N-demethylase activity was affected the most whereas aminopyrine N-demethylase and hexobarbital oxidase activities were only marginally affected. Furthermore, these differences in responsiveness seem to be a delayed event, since hepatic aminopyrine N-demethylase activity in rats castrated at birth did respond to androgen stimulation during the prepubertal period and became insensitive to this same androgen stimulation at adulthood. The effect of neonatal androgen on the apparent Michaelis constant (Km) of ethylmorphine N-demethylase was also studied in the adult rat. Rats castrated at birth had a Km value (0.75 plus or minus 0.15 mM) similar to that of the females (0.95 plus or minus 0.13 mM). However, rats castrated at birth but neonatally treated with androgen and rats castrated at the age of 20 days exhibited Km values (0.29 plus or minus 0.06 and 0.25 plus or minus 0.06 mM, respectively) similar to that of the males (0.35 plus or minus 0.15 mM). The significance of neonatal androgen in the development of hepatic microsomal drug metabolizing enzyme system is discussed.