Developmental alterations in hepatic UDP-glucuronosyltransferase: A comparison of the kinetic properties of enzymes from adult sheep and fetal lambs

The kinetic properties of hepatic microsomal UDP-glucuronosyltransferase were studied in sheep in the perinatal period, using acetaminophen as the aglycone. Kinetic analyses indicated that activity at V max was significantly less in fetal microsomes (113, 135 or 141 days) as compared with the adult sheep. However, these differences between fetal and adult animals were not due simply to smaller amounts of UDP-glucuronosyltransferases catalyzing conjugation of acetaminophen in fetuses versus adults. Thus, the kinetic properties of UDP-glucuronosyltransferase(s) were different in fetus and adult. The “fetal” versus “adult” enzyme had a higher affinity for UDP-glucuronic acid, but a poorer affinity for acetaminophen. Furthermore, enzyme in fetal liver (113 days of gestation) was activated about 30% by the allosteric effector UDP- N-acetylglucosamine, whereas enzyme in adult liver was activated by 500%. These differences between fetal and adult enzymes diminished just prior to parturition (141-day fetus). Enzyme in microsomes from the 141-day fetus responded to UDP- N-acetylglucosamine-like enzyme in adult microsomes and had affinities for substrates that were similar to “adult” enzymes. These data indicate that maturation of the system that glucuronidates acetaminophen is a complex process. It may involve the expression in fetuses of a type of UDP-glucuronosyltransferase that is different from that expressed in the adult. An alternative but not mutually exclusive possibility is that maturation of the glucuronidation system involves modification of enzyme function by alteration of the phospholipids in the immediate environment of UDP-glucuronosyltransferase within the microsomal membrane.