DEVELOPMENT OF HEPATIC MICROSOMAL DRUGOXIDIZING ENZYMES IN IMMATURE MALE AND FEMALE RATS

¹ Department of Pharmacology and Therapeutics and Department of Pediatrics, McGill University, Montreal, Quebec, Canada

The activity of hepatic microsomal drug-metabolizing enzymes is known to be low at birth and for the first four to six weeks of life in rats. The present study examined differences in the pattern of maturation of the capacity for oxidation of a type I substrate (aminopyrine) and a type II substrate (aniline) in male and female rats. The results have been interpreted with respect to the increasing concentration of microsomal cytochrome P-450 and to the increasing activity of the microsomal electron transport enzymes, reduced nicotinamide adenine dinucleotide phosphate (NADPH) cytochrome P-450 reductase and NADPH cytochrome c reductase. The specific activities of microsomal aminopyrine N-demethylase and aniline p-hydroxylase showed a progressive increase in both sexes over a five-week period. After the age of three weeks, male rats demonstrated a higher activity for aminopyrine N-demethylation than did females. For aniline p-hydroxylation there was no significant difference between sexes, and both sexes achieved adult specific activity at five weeks of age. In males, the pattern of maturation of drug oxidation followed most closely the increasing mean specific activity of NADPH cytochrome P-450 reductase, while in females there was a closer relationship with the increasing mean specific activity of NADPH cytochrome c reductase. In both sexes there was poor correlation between increasing drug-oxidative activity and the increasing concentration of cytochrome P-450. In adult rats, the mean specific activities of aminopyrine N-demethylase and NADPH cytochrome P-450 reductase and the mean concentration of cytochrome P-450 were significantly lower in the female. For these three parameters, the significant sex-related difference developed between two and three weeks of age. The results obtained have been interpreted hypothetically to provide an estimate of the error incurred when drug dosage in newborn rats is calculated on the basis of body weight relative to adult weight.