ALTERATIONS IN RAT HEPATIC DRUG-METABOLISM DURING PREGNANCY AND LACTATION

The hepatic microsomal drug metabolism during pregnancy and lactation was studied. Four days post partum, the concentrations of cytochrome P 450 and cytochrome b5 were reduced by 50% when compared with pregnant rats, at day 10 of gestation. Within this time period the N-demethylat ion of aminopyrine, the rate of aldrin epoxidation and the N-demethyla tion of demethylnitrosamine was reduced by 53, 74 and 21 %, respective ly. However, the rates of ethoxyresorufin-O-deethylation did not diffe r amongst both groups and the deethylation of 4-nitroanisole and the 4 -hydroxylation of aniline was increased by 71 and 31%, respectively in lactating rats. Furthermore, the activities of UDP-glucuronyltransfer ase and glutathione S-transferase were increased by 21 and 27%, but th ose of epoxide hydrolase were reduced by 85%. Western immunoblot analy sis of microsomal proteins obtained from pregnant and lactating rats s hows that only proteins encoded by the genes of CYP2C6 and CYP3A1 are expressed at detectable levels, whereas the expression of CYP1A1, CYP1 A2, CYP2A1, CYP2B1, CYP2E1 and CYP4A1 was not detectable in pregnant a nd lactating rats at a protein loading of 3 mug total protein per well . In contrast, in northern blot hybridization experiments, detectable amounts of mRNA of the above named isoenzymes were measurable, but at varying intensities. Based on the northern blot hybridization analysis , an approximate 4-fold and 3-fold increase in CYP2A1 mRNA and CYP3A1 mRNA was found, when lactating rats were compared with female controls or pregnant rats, at day 10 of gestation.