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Low glutathione S-transferase dogs

  • Toxicokinetics and Metabolism
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Abstract

Liver and kidney glutathione S-transferase (GST) activities to 1,2-dichloro-4-nitrobenzene (DCNB) as a substrate (GST-D activities) were measured in 280 dogs from five different breeders, and significant individual differences in this activity were observed in both organs. Interestingly, 34 out of the 280 dogs (i.e. 12.1%) were those in which liver GST-D activities were less than 10 nmol/min per mg cytosolic protein, “low GST dogs”, and the other dogs were classified as “middle” and “high” GST dogs for which the liver GST-D activities were 10–80 and >80 nmol/min per mg protein, respectively, and occurred at similar percentages (41.4% for the middle GST dog and 46.4% for the high GST dog). Furthermore, the existence of the low GST dogs was not limited to one particular breeder. There was a good correlation (r=0.910) between the liver and kidney GST-D activities, showing low activity in not only the liver but also the kidney in the low GST dogs. Although liver GST activity to 1-chloro-2,4-dinitrobenzene as a substrate (GST-C activity), catalyzed by various GST isozymes in dogs, was significantly correlated with liver GST-D activity, GST-C activity showed more than 450 nmol/min per mg protein even in the low GST dogs. There was no significant difference in cytochrome P450 content, 7-ethoxycoumarin O-deethylase activity or UDP-glucuronosyltransferase activity to p-nitrophenol as a substrate between low GST dogs and the other dogs. Finally, remarkably high plasma concentrations of DCNB were observed in the low GST dogs after single doses of DCNB at 5 or 100 mg/kg. The individual differences in GST-D activity are probably attributable to the content and/or activity of the theta class GST isozyme YdfYdf since it has been reported that glutathione conjugation of DCNB is specifically catalyzed by GSTYdfYdf in dogs. In conclusion, we identified a number of low GST dogs in which the GST-D activities were not observed either in vivo or in vitro. The feasibility of using a single low dose of DCNB to phenotype dogs based on GST-D activity was confirmed. It was also suggested that low GST dogs have high susceptibility, including unexpected toxicity or abnormal exposure, to chemicals metabolized by GSTYdfYdf.

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Acknowledgements

We are particularly grateful to Dr. Koichi Hirano, Mr. Yasumitsu Nakatsugawa and Mr. Hitoshi Onishi for their advice and technical assistance. We also wish to express our thanks to Ms Caroline Bertorelli for proof-reading of this manuscript. We declare that this experiment complied with the current laws of Japan.

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  1. Medicinal Safety Research Laboratories, Sankyo Co. Ltd., 717 Horikoshi, Fukuroi-shi, 437-0065, Shizuoka, Japan

    Toshiyuki Watanabe, Tomomi Sugiura, Sunao Manabe, Wataru Takasaki & Yoshihiko Ohashi

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  1. Toshiyuki Watanabe
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  2. Tomomi Sugiura
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  3. Sunao Manabe
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  4. Wataru Takasaki
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  5. Yoshihiko Ohashi
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Correspondence to Toshiyuki Watanabe.

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Watanabe, T., Sugiura, T., Manabe, S. et al. Low glutathione S-transferase dogs. Arch Toxicol 78, 218–225 (2004). https://doi.org/10.1007/s00204-003-0536-x

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