Altered sex differentiation of hepatic ethylmorphine N-demethylation in the male rat following neonatal methadone exposure.

Since acute methadone treatment reduces serum androgen levels in adult male rats, we have investigated the effect of exposure of neonatal rats to methadone (M) on the "neonatal imprinting" of hepatic monooxygenase by testosterone. The kinetic constants for ethylmorphine N-demethylation (ED) in hepatic microsomes of adult rats are sex-related (female Km greater than male Km and male Vmax greater than female Vmax). Treatment of male neonates with M (2.5 mg/kg, sc) during the first 5 postnatal days resulted in an elevation of the Km, but no significant changes in the Vmax for ED in adult life. The M-induced "feminization" of the Km for ED could be prevented by a single dose of testosterone propionate (TP) given to the neonates on day 2 following birth. M treatment also reduced in a reversible manner neonatal serum androgen levels: Decreased androgen levels were not observed beyond the fifth postnatal day. These data suggest that the feminizing effect of M may be related to a reversible chemical castration effect during a critical neonatal period. Our studies also show that the imprinting of the Km and Vmax for ED do not occur during the identical period.