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.
31Birds are exposed to many xenobiotics during their lifetime. For accurate prediction of 32 xenobiotic-induced toxic effects on avian species, it is necessary to understand metabolic 33 capacities in a comprehensive range of bird species. However, there is a lack of information 34 about avian xenobiotic metabolizing enzymes (XMEs), particularly in wild birds. Uridine 35 diphosphate glucuronosyltransferase (UGT) is an XME that plays an important role in phase II 36 metabolism in the livers of mammals and birds. This study was performed to determine the 37 characteristics of UGT1E isoform in avian species, those are related to mammals UGT 1A. To 38 understand the characteristics of avian UGT1E isoforms, in vitro metabolic activity and genetic 39 characteristics were investigated. Furthermore, mRNA expression levels of all chicken UGT1E 40 isoforms were measured. On in vitro enzymatic analysis, the white-tailed eagle, great horned 41 owl, and Humboldt penguin showed lower UGT-dependent activity than domestic birds. In 42 synteny analysis, carnivorous birds were shown to have fewer UGT1E isoforms than 43 herbivorous and omnivorous birds, which may explain why they have lower in vitro UGT 44 activity. These observations suggested that raptors and seabirds, in which UGT activity is low, 45 may be at high risk if exposed to elevated levels of xenobiotics in the environment. 46 Phylogenetic analysis suggested that avian UGT1Es have evolved independently from 47 mammalian UGT1As. We identified the important UGT isoforms, such as UGT1E13, and 48 suspected their substrate specificities in avian xenobiotic metabolism by phylogenetic and 49 quantitative real-time PCR analysis. This is the first report regarding the genetic characteristics 50 and interspecies differences of UGT1Es in avian species.51 52
Cytochrome P450s are among the most important xenobiotic metabolism enzymes that catalyze the metabolism of a wide range of chemicals. Through duplication and loss events, CYPs have created their original feature of detoxification in each mammal. We performed a comprehensive genomic analysis to reveal the evolutionary features of the main xenobiotic metabolizing family: the CYP1-3 families in Carnivora. We found specific gene expansion of CYP2Cs and CYP3As in omnivorous animals, such as the brown bear, the black bear, the dog, and the badger, revealing their daily phytochemical intake as providing the causes of their evolutionary adaptation. Further phylogenetic analysis of CYP2Cs revealed Carnivora CYP2Cs were divided into CYP2C21, 2C41, and 2C23 orthologs. Additionally, CYP3As phylogeny also revealed the 3As’ evolution was completely different to that of the Caniformia and Feliformia taxa. These studies provide us with fundamental genetic and evolutionary information on CYPs in Carnivora, which is essential for the appropriate interpretation and extrapolation of pharmacokinetics or toxicokinetic data from experimental mammals to wild Carnivora.
The UDP-glucuronosyltransferase (UGT) gene family is responsible for the transfer of glucuronic acid to exogenous and endogenous chemicals. Based on the highly diversified number of genes, the mammalian UGT1A and UGT2B subfamily genes are believed to be involved in the conjugation reactions of xenobiotic metabolism. However, it is speculated that the UGT2 family genes are not involved in the xenobiotic metabolism of avian species due to the less diverse number of genes. In this study, we aimed to investigate the evolutionary history of mammalian UGT1 and UGT2 family genes and determine when the diversification of UGT2B genes occurred. We also attempted to identify the main factors responsible for the diversification of UGT genes. By examining the genomic information and feeding habits of 67 species representing each mammalian family, we discovered that the UGT2B genes emerged in the Eutheria on or after Cretaceous period and that their number were higher in plant-eating mammals (herbivore or omnivore) than in carnivorous mammals. We also found that the UGT2B genes in some herbivorous mammals underwent positive selection. In contrast, the diversity of the UGT1 family genes was inherited from the common ancestor of birds and mammals. Thus, our findings suggest that the emergence of angiosperms (flowering plants) and the occurrence of “animal–plant warfare” influenced the evolution of this gene family involved in the xenobiotic metabolism of eutherians. Furthermore, future research investigating the marsupials and birds that do not possess UGT2B genes is required to elucidate the mechanisms underlying the metabolism of chemical substances in these species.
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