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Low glutathione S-transferase dogs
Toshiyuki Watanabe1, Tomomi Sugiura, Sunao Manabe
1Medicinal Safety Research Laboratories, Sankyo Co. Ltd., 717 Horikoshi, Fukuroi-shi, 437-0065 Shizuoka, Japan. tywata@fuku.sankyo.co.jp
Archives of Toxicology
|December 20, 2003
Summary
Researchers identified "low GST dogs" with significantly reduced glutathione S-transferase (GST) activity. These dogs exhibit higher plasma concentrations of DCNB, indicating potential increased susceptibility to certain chemicals.
Area of Science:
- Veterinary Pharmacology
- Biochemistry
- Toxicology
Background:
- Glutathione S-transferases (GSTs) are crucial enzymes involved in xenobiotic detoxification.
- Individual variations in GST activity can influence an organism's susceptibility to chemical toxicity.
- Understanding these variations is essential for assessing drug metabolism and environmental exposure risks in animals.
Purpose of the Study:
- To investigate individual differences in liver and kidney glutathione S-transferase (GST) activity in dogs using 1,2-dichloro-4-nitrobenzene (DCNB) as a substrate.
- To identify and characterize dogs with significantly low GST-D activity.
- To explore the implications of low GST-D activity on DCNB metabolism and potential chemical susceptibility.
Main Methods:
- Measurement of liver and kidney GST-D activities in 280 dogs from five breeders.
- Classification of dogs into "low", "middle", and "high" GST-D activity groups.
- Correlation analysis between liver and kidney GST-D activities.
- Assessment of other metabolic enzyme activities (cytochrome P450, UDP-glucuronosyltransferase) and plasma DCNB concentrations after DCNB administration.
Main Results:
- Significant individual differences in GST-D activity were observed in both liver and kidney.
- 12.1% of dogs were classified as "low GST dogs" with <10 nmol/min per mg cytosolic protein liver GST-D activity.
- Low GST dogs exhibited significantly higher plasma DCNB concentrations after dosing, suggesting impaired metabolism.
- GST-D activity correlated well with liver and kidney activity, and was specifically linked to the theta class GST isozyme Yd(f)Yd(f).
Conclusions:
- A distinct subpopulation of "low GST dogs" was identified, characterized by reduced GST-D activity.
- A single low dose of DCNB can effectively phenotype dogs based on GST-D activity.
- Low GST dogs may possess heightened susceptibility to chemicals metabolized by GSTYd(f)Yd(f), leading to potential unexpected toxicity or adverse effects.