Stereochemical heterogeneity of hepatic UDP-glucuronosyltransferase activity in rat liver microsomes

Rat liver UDP glucuronosyltransferase activities may be divided into at least two groups with differential responses towards substrates. This paper deals with an attempt to describe on what chemical basis the two groups may be distinguished. We studied the glucuronidation of 24 substrates in liver-microsomes of Sprague-Dawley rats pretreated with 3-methylcholanthrene or phenobarbital. The conjugation of 11 substrates was stimulated most strongly by 3-methylcholanthrene and that of the others, by phenobarbital. The estimated thickness of the molecules in their most likely conformation was below 4 Å for molecules of the first group and more than 4 Å for the second. The thickness or the bulkiness of the molecules seems to play an important role. However, for phenol substituted in the position 2, a steric effect or intramolecular interactions may change the substrate's classification within these two groups. It was also noticed that phenobarbital stimulated more than 3-methylcholanthrene the glucuronidation of the corresponding hydroxylated metabolite.