Heterogeneity of hepatic microsomal UDP-glucuronosyltransferase activities. Conjugations of phenolic and monoterpenoid aglycones in control and induced rats and guinea pigs.

In this report we present evidence that the heterogeneity of hepatic microsomal UDP-glucuronosyltransferase(s) (UDPGT) activities depends on the chemical structures of the aglycones as well as their biophysical constants. Three animal models were used: Wistar rats, which have active UDPGTs; Gunn rats, in which some of the UDPGT activities are reduced, but which can be induced by phenobarbital; and guinea pigs. In Wistar rats, we found that some coumarins were poor substrates of UDPGT (GT1) and that twenty monoterpenoid alcohol activities showed typical phenobarbital-inducible behavior. In Gunn rats, we showed that substitution of the phenolic aglycone by bulky (alkyl- or methoxy-) groups in the 2-position of the phenolic ring decreased UDPGT (GT1) activity, whereas substitution in the 4-position resulted in an increase in this activity. We also showed that, in this particular strain, activities toward terpenes were less affected than activities toward flat (aromatic) aglycones. Induction by phenobarbital in Gunn rats increased the activity and limited the deficiency for monoterpenoid alcohols. In guinea pigs, we confirmed that phenobarbital selectively increased the activities of UDPGT towards twenty monoterpenoid alcohols without affecting other typical phenobarbital-induced activities such as those for conjugation of morphine. Finally, we showed that orientation of the aglycone molecule in the active site was apparently related to its dipole moment and that the distance between "acceptor-oxygen" (hydroxyl) and the carbons out of the general plane of the molecule was an important factor. These studies clearly suggest that rat and guinea pig contain a UDPGT(monoterpenoid alcohols) with restricted specificities and also that UDPGT(GT1) comprises at least two or three different isoenzymes, each with a slightly different restricted specificity towards flat aromatic aglycones.