UDP-Glucuronosyltransferases (UGTs) are classified into three subfamilies, Ugt1a, 2b, and 2a, in mice. In the Ugt1a subfamily, Ugt1a1 and 1a6 appear to correspond to human UGT1A1 and 1A6. The mouse is an important animal used for investigations but the substrate specificities of Ugt isoforms belonging to the 2b subfamily in mice remain largely unknown. To address this issue, we characterized the substrate specificity of all isoforms of the Ugt2b subfamily expressed in mouse liver. The cDNAs of Ugt1a1, Ugt2a3 and all the Ugt2b isoforms expressed in the liver were reverse-transcribed from total RNA of male FVB-mouse liver and amplified. A baculovirus-Sf9 cell system for expressing each Ugt was established. Of all the Ugts examined, Ugt2b34, 2b36, and 2b37 exhibited the ability to glucuronidate morphine with Ugt2b36 the most active in this regard. Ugt1a1, but also Ugt2b34, 2b36, and 2b37 to a lesser extent preferentially catalyzed the glucuronidation of 17β-estradiol on the 3-hydroxyl group (E3G). With these isoforms, E3G formation by Ugt1a1 was efficient. However, Ugt2b5 exhibited a preference for the 17β-hydroxyl group (E17G). Ugt2b1 and Ugt2a3 formed comparable levels of E3G and E17G. Ugt2b1 and 2b5 were the only isoforms involved in chloramphenicol glucuronidation. As Ugt2b36 is highly expressed in the liver, it is most likely that Ugt2b36 is a major morphine Ugt in mouse liver. Regarding E3G formation, Ugt1a1, like the human homologue, seems to play an important role in the liver.
- The American Society for Pharmacology and Experimental Therapeutics