Odorant signal termination by olfactory UDP glucuronosyl transferase

Abstract

The onset of olfactory transduction has been extensively studied, but considerably less is known about the molecular basis of olfactory signal termination. It has been suggested that the highly active cytochrome P450 monooxygenases of olfactory neuroepithelium are termination enzymes, a notion supported by the identification and molecular cloning of olfactory-specific cytochrome P450s (refs. 13-16). But as reactions catalysed by cytochrome P450 (refs 17, 18) often do not significantly alter volatility, lipophilicity or odour properties, cytochrome P450 may not be solely responsible for olfactory signal termination. In liver and other tissues, drug hydroxylation by cytochrome P450 is frequently followed by phase II biotransformation, for example by UDP glucuronosyl transferase (UGT), resulting in a major change of solubility and chemical properties. We report here the molecular cloning and expression of an olfactory-specific UGT. The olfactory enzyme, but not the one in liver microsomes, shows preference for odorants over standard UGT substrates. Furthermore, glucuronic acid conjugation abolishes the ability of odorants to stimulate olfactory adenylyl cyclase. This, together with the known broad spectrum of drug-detoxification enzymes, supports a role for olfactory UGT in terminating diverse odorant signals.

Xenobiotic Metabolism in Mice Lacking the UDP-Glucuronosyltransferase 2 Family

“…Ugt2a1 and Ugt2a2 are expressed in the nasal epithelium, and studies using recombinant enzymes have shown that they are able to conjugate odorants. This is hypothesized to be important in the termination of odorant signaling and preventing receptor desensitization (Lazard et al, 1991;Sneitz et al, 2009). The DUgt2 mouse line should allow this hypothesis to be tested, both in vitro using cultured nasal epithelial cells and in vivo using odordependent behavioral paradigms (Friedrich, 2006).…”

Elevated Serum Bisphenol A Levels under Hyperandrogenic Conditions may be Caused by Decreased UDP-glucuronosyltransferase Activity

“…The liver is a major site of glucuronidation as evidenced by the quantitative analysis. However, extrahepatic glucuronidation is also known to occur in organs such as the lung, kidney, gastrointestinal mucosa, prostate and olfactory epithelium [28][29][30][31][32][33]. The overall quantitative contribution of extrahepatic glucuronidation is much smaller compared with hepatic glucuronidation.…”

Pharmacogenomics of human UDP-glucuronosyltransferase enzymes

“…The biological function of UGT2As was proposed to be the termination of the odorant signals, although it is not limited to this function since they are expressed in the liver, small intestine, brain and fetal lung. [102][103][104] The wide range of substrates for human UGTs includes compounds of diverse chemical structures. Several studies have described the overlapping substrate specificities of UGT proteins.…”