Substrate-selective induction of rabbit hepatic UDP-glucuronyltransferases by ethanol and other xenobiotics

Abstract

Male New Zeland white rabbits were treated with various inducers of hepatic metabolism enzymes to characterize the induction of UDP-glucuronyltransferase (UDP-GT) enzymes. Rabbits were pretreated with phenobarbital, 1,1,1-trichloro-2,2-bis( p-chlorophenyl)ethane (DDT), 3-methylcholanthrene, β-naphthoflavone, Aroclor 1254, ethanol, trans-stilbene oxide, pregnenolone-16α-carbonitrile, or clofibric acid. Hepatic microsomes from treated and control animals were incubated with the GT 1-type substrates, p-nitrophenol and 1-naphthol; the GT 2-type substrate, morphine; and the steroid substrate, estrone. Compared to the rat, the rabbit was particularly resistant to UDP-GT induction. Ethanol was the most potent inducer for both GT 1 and GT 2 activities, but it failed to induce steroid (estrone, estradiol, and testosterone) UDP-GT activities. Ethanol pretreatment increased oxazepam-GT but it decreased bilirubin-GT activity. 3-Methylcholanthrene (3MC) and β-nphthoflavone (BNF) are the prototypic GT 1 inducers in the rat, but 3MC caused no induction of GT 1 activity and BNF caused induction of both GT 1 and GT 2 activities in the rabbit. None of the xenobiotic pretreatments increased the hepatic microsomal glucuronidation of estrone. These results demonstrate that the induction of UDP-GT activities, and the use of this phenomenon to classify UDP-GT forms, is somewhat species-specific and cannot necessarily be extrapolated from rats to other species. In addition, the substrate selectivity of ethanol-induced microsomal UDP-GT was established.