Received for publication November 21, 2006.
Revised March 15, 2007.
Accepted for publication March 27, 2007.

Effect of perinatal low protein diets on the ontogeny of select hepatic cytochrome P450 enzymes and cytochrome P450 reductase in the rat

Abstract

The present study administered two low protein diets (LPD) to rats during pregnancy and lactation, and determined their effect on the ontogeny of select hepatic cytochrome P450 (CYP) isoforms 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. Perinatal LPD altered the activities of a number of CYP isoforms in 28 day old male and female offspring. However nutritional rehabilitation abolished most of these changes as evidenced by lack of differences between the five groups in the activities of CYP isoforms in either 65 day or 150 day old offspring. Interestingly, 58 day old female offspring of the LM76 group, but not the L93 group, exhibited shorter hexobarbital sleep time than the purified control group. However, hexobarbital hydroxylase activity and amount of CYP2C12 protein, an important CYP isoform involved in hexobarbital metabolism in females, were unchanged. This suggests that the decrease in hexobarbital sleep time in this group is not due to an increase in the activity of hexobarbital metabolizing enzymes. In summary, perinatal LPDs produced transient alteration in activities of select hepatic CYPs, and resulted in a gender and diet dependent long-term alteration in hexobarbital pharmacodynamics.

Key words: cytochrome P450, cytochrome P450 isoforms, developmental pharmacology, enzyme kinetics, liver microsomes