Species Differences in UDP-Glucuronosyltransferase Activities in Mice and Rats

Abstract

ABSTRACT:UDP-glucuronosyltransferases (UGTs), expressed in various tissues including liver and intestine, catalyze phase II metabolic biotransformation. There is little information on species differences between mice and rats in UGT activities, especially in intestine. The purpose of the present study was to clarify the species differences between mice and rats in UGT activities using duodenal and liver microsomes. For estradiol 3-O-glucuronidation in duodenal microsomes, the kinetic data in mice were fit to the Hill equation. However, the Hill coefficient was low in rats (n ‫؍‬ 1.1), suggesting that rat estradiol 3-O-glucuronidation followed the Michaelis-Menten equation rather than the Hill equation. For 4-nitrophenol (4-NP) O-glucuronidation, the K m values were different between mice and rats. The intrinsic clearance (CL int ) values for mycophenolic acid (MPA) O-and morphine 3-O-glucuronidation in male mouse duodenum were 3-and 17-fold lower than those in rat, respectively. In male liver, the CL int values for 4-NP O-, propofol O-, MPA O-, and morphine 3-O-glucuronidation and the CL max value for 4-methylumbelliferone O-glucuronidation in mice were higher than those in rats. The CL max value for estradiol 3-O-glucuronidation in mice was lower than that in rats. Also, there were strain differences among C57BL/6J, BALB/c, C3H/HeJ, DBA/2, ddY, and ICR mice in UGT activities in duodenum. We clarified that the species differences in UGT activity evaluated by the CL int or CL max values in liver and duodenum varied according to the substrate.

Regioselective Glucuronidation of Tanshinone IIa after Quinone Reduction: Identification of Human UDP-Glucuronosyltransferases, Species Differences, and Interaction Potential

“…In view of the large species differences in producing M1 and M2, we consider that the specific UGT isoforms responsible for TSA glucuronidation may be different across various species. Such evidence obtained from this study and previous reports (Mano et al, 2008;Shiratani et al, 2008) suggests that the species differences of UGT-catalyzed reactions may be much more complicated and frequent than that for P450s.…”

“…Compared with liver, the overall intestinal glucuronidation clearance was approximately 2-fold lower, which was not surprising considering that the glucuronidation activities of most substrates in intestine were relatively lower than those in liver (Shiratani et al, 2008). However, the overall contribution of intestinal glucuronidation of the oral ingested TSA may be much higher than that of liver because of the longer retention and higher exposure in intestine (Hao et al, 2007).…”

“…Obvious species differences of the UGT1A9 gene were found; for example, human UGT1A9 and mouse Ugt1a9 are functional, whereas rat UGT1A9 is a pseudogene (Mackenzie et al, 2005;Shiratani et al, 2008). Thus, it is questionable which UGT isoform in rats is mainly involved in the TSA glucuronidation.…”

“…Using CL int M2/M1 as a regioselective index, it was interesting to find that the M1 and M2 production in rats (1.0) was almost identical, whereas a significant but opposite regioselectivity was observed between humans (0.7) and mice (1.3). It seems that regioselectivity and species differences are very common for UGTs because similar phenomena were found for many other UGT substrates (Kaji and Kume, 2005a,b;Shiratani et al, 2008;Rouguieg et al, 2010), but the underlying mechanism was unclear until now.…”

In Vitro Glucuronidation of the Antibacterial Triclocarban and Its Oxidative Metabolites

“…All tested microsomes showed a low K M and a high V max , resulting in a high apparent intrinsic clearance (Table 3). The clearance of 2Ј-OH-TCC by MLM and RLM was comparable or higher than the reported values for reference UGT substrates including 4-methylumbelliferone, para-nitrophenol, propofol, and mycophenolic acid (Shiratani et al, 2008). With a conversion rate of 1.74 ml ⅐ mg Ϫ1 ⅐ min…”