p-Aminophenol-induced hepatotoxicity in hamsters: role of glutathione.
p-Aminophenol (PAP) is a widely used industrial chemical and a known nephrotoxin. Recently, it was found to also cause hepatotoxicity and glutathione (GSH) depletion in mice. The exact mechanism of liver toxicity is not known. The aims of this study were to determine whether PAP can cause acute hepatotoxicity in hamsters and to further investigate the role of GSH in PAP-induced toxicity. PAP was administered ip to hamsters in doses of 200-800 mg/kg. Liver damage at 24 h after PAP administration was assessed by elevations in plasma enzyme activities and histopathologic examination. GSH and cysteine (Cys) levels in liver at 4 h were determined by HPLC. PAP decreased hepatic GSH concentration to 8% and Cys to 30% of vehicle control values. It increased plasma glutamic pyruvic transaminase (GPT) activity by 47-fold and sorbitol dehydrogenase (SDH) activity by 113-fold. PAP also caused severe centrilobular hepatocellular necrosis. 2(RS)-n-Propylthiazolidine-4(R)-carboxylic acid (PTCA), a Cys precursor, attenuated the PAP-induced decreases in hepatic sulfhydryl levels; GSH and Cys were 39% and 78% of vehicle controls, respectively. PTCA also attenuated the PAP-induced elevations in plasma enzyme activities and hepatic necrosis. It was concluded that PAP hepatotoxicity is associated with depletion of hepatic GSH and can be prevented by PTCA.
Fu
Xin
X
Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40292, USA.
Chen
Theresa S
TS
Ray
Mukunda B
MB
Nagasawa
Herbert T
HT
Williams
Walter M
WM
D000410:Alanine Transaminase / Q000097:blood / Q000187:drug effects; D000627:Aminophenols / Q000633:toxicity*; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D006224:Cricetinae; D003545:Cysteine / Q000032:analysis / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D064420:Drug-Related Side Effects and Adverse Reactions / Q000139:chemically induced*; D005978:Glutathione / Q000378:metabolism*; D007700:Kinetics; D007064:L-Iditol 2-Dehydrogenase / Q000097:blood / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008708:Methemoglobinemia / Q000139:chemically induced; D020011:Protective Agents / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology
D000627:Aminophenols; D020011:Protective Agents; D013844:Thiazoles; C101197:2-n-propylthiazolidine-4-carboxylic acid; D007064:L-Iditol 2-Dehydrogenase; D000410:Alanine Transaminase; D005978:Glutathione; D003545:Cysteine