Effect of maternal low protein diet during pregnancy and lactation on drug metabolism in the offspring

Administration of a low protein diet (LPD) to pregnant rats is often used to produce fetal growth retardation and examine its consequences in the adult offspring. The present study administered two LPDs to rats during pregnancy and lactation, and determined their effect on the food intake and reproductive performance in the dams, and body weight and ontogeny of select hepatic cytochrome P450 (CYP) isozymes in their offspring. The L93 and LM76 LPDs were derived from the American Society of Nutrition recommended AIN93G, and a modified version of the AIN76A purified control diets respectively. The LPDs contained 8% crude protein in the form of casein while the purified control diets contained 19% casein. A regular cereal based diet (NP) was also included and therefore a total of five groups were tested. Pups in all five groups were weaned onto a regular NP diet on postnatal day 28. Blood urea nitrogen concentrations and food consumption (especially during the lactation period) in dams of both LPD groups were lower than their respective controls. This finding suggests that in lactating rats both LPDs produce energy malnourishment in addition to protein deficiency. Offspring of both LPD groups exhibited lower birth weights compared to their respective controls. Despite initiating nutritional rehabilitation at weaning (day 28), perinatal administration of both LPDs produced long term reductions in the body weight of male offspring. Interestingly, in the female offspring one of the LPDs reduced birth weight for the entire duration of the study (180 days) while the other LPD produced a relatively short term reduction in body weight. Perinatal LPD altered the activities of CYP2E1, testosterone 2alpha hydroxylase, testosterone 7alpha hydroxylase, ethoxyresorufin O-dealkylase and cytochrome P450 reductase in 28 day old offspring. However nutritional rehabilitation abolished most of these changes as evidenced by the lack of differences in the activities of CYP isozymes in either 65 day or 150 day old offspring between the five groups. Interestingly, 58 day old female offspring of LM76 group, but not L93 group, exhibited shorter hexobarbital sleep time than the purified control group suggesting an induction in the hexobarbital metabolizing enzymes. However, hexobarbital hydroxylase activity and protein amount of CYP2C12, one of the important CYP isozymes involved in hexobarbital metabolism in females, were unchanged. In summary, perinatal LPDs produced transient alterations in the hepatic CYP activities, but they produced gender and diet dependent long term decrease in hexobarbital induced sleep time and body weight.