Systematic identification and characterization of glutathione S-transferases in cynomolgus macaque

Uno, Yasuhiro; Murayama, Norie; Kunori, Mutsuki; Yamazaki, Hiroshi

doi:10.1016/j.bcp.2013.06.022

Cited by 17 publications

(25 citation statements)

References 27 publications

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“…Mouse liver is reported to have a higher level of glutathione-S-transferase (GST) activity (149 ± 13 nmol/min/ mg) compared with rat (87 ± 10 nmol/min/mg) and human (25 ± 4 nmol/min/mg) (Pacifici et al, 1981) and coupled with the lower gamma glutamyltranspeptidase activity in mice and rats (Sulakhe & Lautt, 1985) supports the observation for a greater abundance of M5 than M4. Monkey GST enzymes have been reported to have exon-intron structures similar to the human orthologs, which may explain the similarities in the monkey and human pathways (Uno et al, 2013). The proposed mechanism for the formation of these particular metabolites follows the generation of an arene oxide (Castellino et al, 2013), a potential bioreactive intermediate.…”

Section: Discussionmentioning

confidence: 97%

The comparative disposition and metabolism of dolutegravir, a potent HIV-1 integrase inhibitor, in mice, rats, and monkeys

et al. 2014

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1. Plasma clearance of dolutegravir, an unboosted HIV-1 integrase inhibitor, was low in rat and monkey (0.23 and 2.12 mL/min/kg, respectively) as was the volume of distribution (0.1 and 0.28 L/kg, respectively) with terminal elimination half-life approximately 6 h. Dolutegravir was rapidly absorbed from oral solution with a high bioavailability in rat and monkey (75.6 and 87.0% respectively), but solubility or dissolution rate limited when administered as suspension. 2. Dolutegravir was highly bound (>99%) to serum proteins in rat and monkey, similar to binding to plasma and serum proteins in human. Radioactivity was associated with the plasma versus cellular components of blood across all species. 3. Following oral administration to rats, [(14)C]dolutegravir-related radioactivity was distributed to most tissues, due in part to high permeability; however, because of high plasma protein binding, tissue to blood ratios were low. In mouse, rat and monkey, the absorbed dose was extensively metabolized and secreted into bile, with the majority of the administered radioactivity eliminated in feces within 24 h. 4. The primary route of metabolism of dolutegravir was through the formation of an ether glucuronide. Additional biotransformation pathways: benzylic oxidation followed by hydrolysis to an N-dealkylated product, glucose conjugation, oxidative defluorination, and glutathione conjugation.

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Section: Discussionmentioning

confidence: 97%

The comparative disposition and metabolism of dolutegravir, a potent HIV-1 integrase inhibitor, in mice, rats, and monkeys

et al. 2014

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“…The GSTM gene family varies in composition among primates with unknown functional consequences. For example, a locus-specific study has shown that the GSTM1 was not expressed as a functional gene in a cynomolgus macaque ( Macaca fascicularis ) [ 30 ]. Rapid change in the number and type of gene families to fine-tune the functional repertoire has been shown, especially within the context of host-pathogen arms race [ 31 ].…”

Section: Introductionmentioning

confidence: 99%

Complex evolution of the GSTM gene family involves sharing of GSTM1 deletion polymorphism in humans and chimpanzees

et al. 2018

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BackgroundThe common deletion of the glutathione S-transferase Mu 1 (GSTM1) gene in humans has been shown to be involved in xenobiotic metabolism and associated with bladder cancer. However, the evolution of this deletion has not been investigated.ResultsIn this study, we conducted comparative analyses of primate genomes. We demonstrated that the GSTM gene family has evolved through multiple structural variations, involving gene duplications, losses, large inversions and gene conversions. We further showed experimentally that the GSTM1 was polymorphically deleted in both humans and also in chimpanzees, through independent deletion events. To generalize our results, we searched for genic deletions that are polymorphic in both humans and chimpanzees. Consequently, we found only two such deletions among the thousands that we have searched, one of them being the GSTM1 deletion and the other surprisingly being another metabolizing gene, the UGT2B17.ConclusionsOverall, our results support the emerging notion that metabolizing gene families, such as the GSTM, NAT, UGT and CYP, have been evolving rapidly through gene duplication and deletion events in primates, leading to complex structural variation within and among species with unknown evolutionary consequences.Electronic supplementary materialThe online version of this article (10.1186/s12864-018-4676-z) contains supplementary material, which is available to authorized users.

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“…Cynomolgus macaques are frequently used in drug metabolism and toxicity studies due to their evolutionary closeness to humans. Our and other groups have identified and characterized a number of drug-metabolizing enzymes, including cytochromes P450, flavin-containing monooxygenases and glutathione S -transferases, and found generally similar molecular characteristics of these enzymes between cynomolgus macaques and humans [ 14 , 16 , 17 , 20 ]. Despite the importance of cynomolgus macaques in drug metabolism studies, AADAC has not been fully investigated partly due to the lack of molecular information on the cynomolgus AADAC.…”

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confidence: 95%

Isolation and characterization of arylacetamide deacetylase in cynomolgus macaques

Uno

Hosokawa

Imai

2015

The Journal of Veterinary Medical Science

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Arylacetamide deacetylase (AADAC), a microsomal serine esterase, hydrolyzes drugs, such as flutamide, phenacetin and rifampicin. Because AADAC has not been fully investigated at molecular levels in cynomolgus macaques, the non-human primate species widely used in drug metabolism studies, cynomolgus AADAC cDNA was isolated and characterized. The deduced amino acid sequence, highly homologous (92%) to human AADAC, was more closely clustered with human AADAC than the dog, rat or mouse ortholog in a phylogenetic tree. AADAC was flanked by AADACL2 and SUCNR1 in the cynomolgus and human genomes. Moreover, relatively abundant expression of AADAC mRNA was found in liver and jejunum, the drug-metabolizing organs, in cynomolgus macaques, similar to humans. The results suggest molecular similarities of AADAC between cynomolgus macaques and humans.

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Systematic identification and characterization of glutathione S-transferases in cynomolgus macaque

Cited by 17 publications

References 27 publications

The comparative disposition and metabolism of dolutegravir, a potent HIV-1 integrase inhibitor, in mice, rats, and monkeys

The comparative disposition and metabolism of dolutegravir, a potent HIV-1 integrase inhibitor, in mice, rats, and monkeys

Complex evolution of the GSTM gene family involves sharing of GSTM1 deletion polymorphism in humans and chimpanzees

Isolation and characterization of arylacetamide deacetylase in cynomolgus macaques

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