Uridine Diphosphate-Glucuronosyltransferase (UGT) 2B Subfamily Interspecies Differences in Carnivores

Takamitsu Kondo; Yoshinori Ikenaka; Shouta M M Nakayama; Yusuke K Kawai; Hazuki Mizukawa; Yoko Mitani; Kei Nomiyama; Shinsuke Tanabe; Mayumi Ishizuka

doi:10.1093/toxsci/kfx072

Uridine Diphosphate-Glucuronosyltransferase (UGT) 2B Subfamily Interspecies Differences in Carnivores

Toxicol Sci. 2017 Jul 1;158(1):90-100. doi: 10.1093/toxsci/kfx072.

Authors

Takamitsu Kondo¹, Yoshinori Ikenaka^{1

2}, Shouta M M Nakayama¹, Yusuke K Kawai³, Hazuki Mizukawa⁴, Yoko Mitani⁵, Kei Nomiyama⁶, Shinsuke Tanabe⁶, Mayumi Ishizuka¹

Affiliations

¹ Laboratory of Toxicology, Department of Environmental Veterinary Science, Graduate School of Veterinary Medicine, Hokkaido University, N18, W9, Kita-ku, Sapporo 060-0818, Japan.
² Water Research Group, Unit for Environmental Sciences and Management, North-West University, Potchefstroom, South Africa.
³ Diagnostic Center for Animal Health and Food Safety, Obihiro University of Agriculture and Veterinary Medicine, Obihiro 080-8555, Japan.
⁴ Department of Environmental Veterinary Science, Graduate School of Veterinary Medicine, Hokkaido University, N18, W9, Kita-ku, Sapporo 060-0818, Japan.
⁵ Field Science Center for Northern Biosphere, Hokkaido University, N11, W10, Kita-ku, Sapporo 060-0811, Japan.
⁶ Center for Marine Environmental Studies (CMES), Ehime University, Bunkyo-cho 2-5, Matsuyama 790-8577, Japan.

PMID: 28453659
DOI: 10.1093/toxsci/kfx072

Abstract

UDP-glucuronosyltransferases (UGTs) are among the most important xenobiotic metabolizing enzymes that conjugate a wide range of chemicals. Previous studies showed that Felidae and Pinnipedia species have very low UGT activities toward some phenolic compounds because of the UGT1A6 pseudogene and small numbers of UGT1A isozymes. In addition to the UGT1As, UGT2Bs isozymes also conjugate various endogenous (eg, estrogens, androgens, and bile acids) and exogenous compounds (opioids, non-steroidal anti-inflammatory drugs, and environmental pollutants). However UGT2B activity and genetic background are unknown in carnivore species. Therefore, this study was performed to elucidate the species differences of UGT2Bs. Using typical substrates for UGT2Bs, UGT activity was measured in vitro. In addition, UGT2B genetic features are analyzed in silico. Results of UGT activity measurement indicate marked species differences between dogs and other carnivores (cats, Northern fur seals, Steller sea lions, Harbor seals, and Caspian seals). Dogs have very high Vmax/Km toward estradiol (17-glucuronide), estrone, lorazepam, oxazepam, and temazepam. Conversely, cats and pinniped species (especially Caspian seals and Harbor seals) have very low activities toward these substrates. The results of genetic synteny analysis indicate that Felidae and pinniped species have very small numbers of UGT2B isozymes (one or none) compared with dogs, rodents, and humans. Furthermore, Felidae species have the same nonsense mutation in UGT2B, which suggests that Felidae UGT2B31-like is also a pseudogene in addition to UGT1A6. These findings of lower activity of UGT2B suggest that Felidae and some pinniped species have very low UGT activity toward a wide range of chemicals. These results are important for Felidae and Pinnipedia species that are frequently exposed to drugs and environmental pollutants.

Keywords: UGTs; carnivore; wildlife; xenobiotics.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Carnivora
Glucuronosyltransferase / genetics
Glucuronosyltransferase / metabolism*
Isoenzymes / genetics
Isoenzymes / metabolism*
Microsomes, Liver / enzymology
Pseudogenes
Substrate Specificity
Xenobiotics / metabolism

Substances

Isoenzymes
Xenobiotics
Glucuronosyltransferase