Low glutathione S-transferase dogs.
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 Yd(f)Yd(f) since it has been reported that glutathione conjugation of DCNB is specifically catalyzed by GSTYd(f)Yd(f) 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 GSTYd(f)Yd(f).
Watanabe
Toshiyuki
T
Medicinal Safety Research Laboratories, Sankyo Co. Ltd., 717 Horikoshi, Fukuroi-shi, 437-0065 Shizuoka, Japan. tywata@fuku.sankyo.co.jp
Sugiura
Tomomi
T
Manabe
Sunao
S
Takasaki
Wataru
W
Ohashi
Yoshihiko
Y
D015660:7-Alkoxycoumarin O-Dealkylase / Q000378:metabolism; D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003600:Cytosol / Q000201:enzymology; D004137:Dinitrochlorobenzene / Q000378:metabolism*; D004285:Dogs; D005260:Female; D014453:Glucuronosyltransferase / Q000378:metabolism; D005982:Glutathione Transferase / Q000172:deficiency* / Q000378:metabolism; D007527:Isoenzymes / Q000172:deficiency / Q000378:metabolism; D007668:Kidney / Q000201:enzymology*; D008099:Liver / Q000201:enzymology*; D008297:Male; D009578:Nitrobenzenes / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics
D004137:Dinitrochlorobenzene; D007527:Isoenzymes; D009578:Nitrobenzenes; D003577:Cytochrome P-450 Enzyme System; C028328:1,2-dichloro-4-nitrobenzene; D015660:7-Alkoxycoumarin O-Dealkylase; D014453:Glucuronosyltransferase; D005982:Glutathione Transferase