The postnatal development of drug-metabolizing enzymes in hepatic, pulmonary and renal tissues of the goat.

Abstract

It is important to study the development of drug biotransformation enzymes, because from a pharmacological and therapeutic point of view these enzymes are responsible for eliminating most drugs. Their concentration at each age is critical when deciding the dose regimen, particularly 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 consequences to the animal. The time course of appearance of these enzymes throughout the life of the animal could be depicted from the study of their ontogeny and therefore the prediction of when the animal would be at risk should be possible. Experiments were designed to measure in vitro, the activity of drug-metabolizing enzymes in liver, lung and kidney of newborn, 1-week-, 4-week and 6-week-old and adult goats. The microsomal monoxygenase activities were measured utilizing substrates designed to characterize the development of the cytochrome P450 (P450). For phase II enzymes, the activity of UDP-glucuronyltransferase towards 1-naphthol and p-nitrophenol was measured in addition to the cytosolic glutathione S-transferase activity towards, 1,2-dichloro 3-nitrobenzene. The results indicated that the newborn goat tissues exhibited very low activity of drug-metabolizing capacity in all pathways studied. These activities increased to the adult values by 6 weeks of age. In general, the development of the mono-oxygenase activities followed the same pattern as the overall P450. The UDP-glucuronyltransferase activity towards both substrates was deficient at birth and surged to above adult values by the first week of age. The toxicologic and pharmacologic implication of the development of these enzyme activities are discussed.