Ursodeoxycholic acid reduces the systemic toxicity of 1,2-dichloro,4-nitrobenzene by stimulating hepatic glutathione S-transferase in mice.
Male C57BL/6 mice were fed with normal diet (ND) or diets containing 0.3 or 0.5% ursodeoxycholic acid (UDCA) for 3 weeks. Glutathione S-transferase (GST) activities in the liver cytosolic fraction of these animals toward 1,2-dichloro,4-nitrobenzene (DCNB) as well as to 1-chloro,2,4-dinitrobenzene (CDNB) were significantly increased in a dose dependent manner in UDCA-treated groups compared with the control (ND-fed) animal group (one-way ANOVA). Reduced glutathione (GSH) levels tended to slightly decrease with UDCA diets but the difference did not attain a statistical significance (P > 0.05, one-way ANOVA). Twenty four hr survival rates after an oral challenge of 3.5 mg/kg of DCNB were significantly higher (P < 0.05, Chi-square test) in the two UDCA fed groups (10/10 for 0.5% group, 8/11 for 0.3% group) compared with the control group (3/11). Thus, UDCA appears to reduce the systemic toxicity of DCNB which is detoxified by the hepatic GST system. Although UDCA has been shown to exert hepatoprotective effects in experimental animals and humans in the past, to the best of our knowledge, the present study is the first report that UDCA reduces the systemic toxicity of a toxicant which is detoxified by the hepatic GST system. Although a direct proof is not available, it is most likely that the reduction of the systemic toxicity of DCNB was achieved by the increase in GST activity caused by UDCA feeding. This finding may open a new research field with regard to the unique biological properties of this bile salt in modulating hepatic detoxifying enzymes.
Kitani
K
K
Radioisotope Research Institute, Faculty of Medicine, University of Tokyo, Japan.
Kanai
S
S
Sato
Y
Y
Ohta
M
M
Nokubo
M
M
D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003600:Cytosol / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D004032:Diet; D004137:Dinitrochlorobenzene / Q000633:toxicity; D005978:Glutathione / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009578:Nitrobenzenes / Q000633:toxicity*; D009929:Organ Size / Q000187:drug effects; D014580:Ursodeoxycholic Acid / Q000008:administration & dosage / Q000494:pharmacology*
D004137:Dinitrochlorobenzene; D009578:Nitrobenzenes; D014580:Ursodeoxycholic Acid; C028328:1,2-dichloro-4-nitrobenzene; D005982:Glutathione Transferase; D000410:Alanine Transaminase; D005978:Glutathione