THE POSTNATAL-DEVELOPMENT OF DRUG-METABOLIZING-ENZYMES IN HEPATIC, PULMONARY AND RENAL TISSUES OF THE GOAT

It is important to study the development of drug biotransformation enz ymes, because from a pharmacological and therapeutic point of view the se enzymes are responsible for eliminating most drugs. Their concentra tion at each age is critical when deciding the dose regimen, particula rly in the neonates who are deficient or have very low levels of these enzymes. From a toxicological perspective, the role of these enzymes varies, with some of them being directly responsible for activation of certain chemicals to reactive intermediates with deleterious conseque nces to the animal. The time course of appearance of these enzymes thr oughout the life of the animal could be depicted from the study of the ir ontogeny and therefore the prediction of when the animal would be a t risk should be possible. Experiments were designed to measure in vit ro, the activity of drug-metabolizing enzymes in liver, lung and kidne y of newborn, 1-week-, 4-week and 6-week-old and adult goats. The micr osomal monooxygenase activities were measured utilizing substrates des igned to characterize the development of the cytochrome P450 (P450). F or phase II enzymes, the activity of UDP-glucuronyltransferase towards 1-naphthol and p-nitrophenol was measured in addition to the cytosoli c glutathione S-transferase activity towards, 1,2-dichloro 3-nitrobenz ene. The results indicated that the newborn goat tissues exhibited ver y low activity of drug-metabolizing capacity in all pathways studied. These activities increased to the adult values by 6 weeks of age. In g eneral, the development of the mono-oxygenase activities followed the same pattern as the overall P450. The UDP-glucuronyltransferase activi ty towards both substrates was deficient at birth and surged to above adult values by the first week of age. The toxicologic and pharmacolog ic implications of the development of these enzyme activities are disc ussed.