Species differences in N-glucuronidation

Abstract

Glucuronidation of amines has been shown to exhibit species differences in vitro and in vivo. Substrates for N-glucuronidation can be classified according to the chemical structures of the resulting glucuronides into two groups: compounds that form non-quaternary N-conjugates, and those that form the quaternary counterparts. For compounds of the former class-such as sulfonamides, arylamines, and alicyclic, cyclic, and heterocyclic amines-species differences appear to be less striking and are of a quantitative nature. No one common laboratory animal species used routinely in metabolism research (e.g. rat, mouse, dog, non-human primate, rabbit, and guinea pig) has been shown to be deficient in N-glucuronidation when all of the substrates studied and reported are taken into consideration. The ability of a species to form N-glucuronides is compound-dependent, although rabbit and guinea pig appear to exhibit the highest capacity for this bioconjugation among preclinical species. For tertiary amines, most notably the tricyclic antidepressant and antihistamine drugs, N-glucuronidation is commonly observed in non-human primates and man. There are examples, however, of quaternary glucuronidation occurring in lower animal species. In exploring species differences in amine conjugation in vivo, it is noted that the apparent absence of N-glucuronides in animal urine may not reflect the inability of that species to form such conjugates, since the N-glucuronides may be excreted in bile. Problems such as degradation or low recoveries commonly encountered in isolation and identification of in vivo metabolites further complicate the interpretation of data. Because of the wide range of pKa values exhibited by various classes of amines, caution also should be exercised for in vitro studies since incubation conditions for N-glucuronidation often are substrate- and species-dependent. Explanations for the species differences observed in N-glucuronidation appear to be emerging as rapid advances are made in the understanding of the glucuronosyltransferases at the molecular level. More information, however, remains to be gathered from the glucuronosyltransferase genes of animal species other than humans before a better understanding of species differences in N-glucuronidation can be achieved.