Precocious development of foetal glucuronidating enzymes induced by glucocorticoids in culture and in utero

Abstract

CONJUGATION with glucuronic acid is the major pathway in vertebrates by which harmful organic compounds are detoxicated. It ensures the excretion of excess endogenous compounds such as steroid hormones, catecholamines and bilirubin, and of a great range of toxic xenobiotics such as drugs, pesticides, industrial pollutants and their metabolites¹. Glucuronidation, however, is virtually absent in the early mammalian foetus and approaches adult levels only in the perinatal period, putting the foetus and newborn at considerable risk from unwise medication or exposure to environmental contaminants. This susceptibility has been demonstrated frequently, often with fatal results^2,3. Defective glucuronidation of endogenous bilirubin is a major cause of human neonatal jaundice and can lead to infant death⁴. Attempts have been made to induce the responsible microsomal enzyme(s), UDP-glucuronyltransferase (EC 2.4.1.17), in cases of prematurity, genetically defective enzyme formation or poisoning by glucuronidogenic compounds; administration of xenobiotic inducers such as phenobarbital has had limited success in neonates and the term foetus^2–5. Adequate treatment of such conditions, however, requires knowledge of endogenous compounds which induce the enzyme perinatally. We report here the first evidence in foetal mammalian tissue of precocious development of UDP-glucuronyltransferase activity and of overall glucuronidation brought about by known compounds of endogenous nature. These findings provide insight into the perinatal development of this important enzyme.