Pretreatment with 1,8-cineole potentiates thioacetamide-induced hepatotoxicity and immunosuppression.
The effect of 1,8-cineole on cytochrome P450 (CYP) expression was investigated in male Sprague Dawley rats and female BALB/c mice. When rats were treated orally with 200, 400 and 800 mg/kg of 1,8-cineole for 3 consecutive days, the liver microsomal activities of benzyloxyresorufin- and pentoxyresorufin-omicron-dealkylases and erythromycin N-demethylase were dose-dependently induced. The Western immunoblotting analyses clearly indicated the induction of CYP 2B1/2 and CYP 3A1/2 proteins by 1,8-cineole. At the doses employed, 1,8-cineole did not cause toxicity, including hepatotoxicity. Subsequently, 1,8-cineole was applied to study the role of metabolic activation in thioacetamide-induced hepatotoxicity and/or immunotoxicity in animal models. To investigate a possible role of metabolic activation by CYP enzymes in thioacetamide-induced hepatotoxicity, rats were pre-treated with 800 mg/kg of 1 ,8-cineole for 3 days, followed by a single intraperitoneal treatment with 50 and 100 mg/kg of thioacetamide in saline. 24 h later, thioacetamide-induced hepatotoxicity was significantly potentiated by the pretreatment with 1,8-cineole. When female BALB/c mice were pretreated with 800 mg/kg of 1,8-cineole for 3 days, followed by a single intraperitoneal treatment with 100 mg/kg of thioacetamide, the antibody response to sheep red blood cells was significantly potentiated. In addition, the liver microsomal activities of CYP 2B enzymes were significantly induced by 1,8-cineole as in rats. Taken together, our results indicated that 1,8-cineole might be a useful CYP modulator in investigating the possible role of metabolic activation in chemical-induced hepatotoxicity and immunotoxicity.
Kim
Nam Hee
NH
College of Pharmacy, Yeungnam University, Kyungsan 712-749, Korea.
Hyun
Sun Hee
SH
Jin
Chun Hua
CH
Lee
Sang Kyu
SK
Lee
Dong Wook
DW
Jeon
Tae Won
TW
Lee
Jae Sung
JS
Chun
Young Jin
YJ
Lee
Eung Seok
ES
Jeong
Tae Cheon
TC
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000917:Antibody Formation / Q000187:drug effects; D001219:Aspartate Aminotransferases / Q000097:blood; D015153:Blotting, Western; D001835:Body Weight / Q000187:drug effects; D002273:Carcinogens / Q000633:toxicity*; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology / Q000473:pathology*; D003511:Cyclohexanols / Q000494:pharmacology*; D004357:Drug Synergism; D004912:Erythrocytes / Q000276:immunology; D000077591:Eucalyptol; D007166:Immunosuppressive Agents / Q000633:toxicity*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008862:Microsomes, Liver / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000378:metabolism; D039821:Monoterpenes / Q000494:pharmacology*; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012756:Sheep / Q000276:immunology; D013853:Thioacetamide / Q000633:toxicity*
D002273:Carcinogens; D003511:Cyclohexanols; D007166:Immunosuppressive Agents; D039821:Monoterpenes; D013853:Thioacetamide; D006899:Mixed Function Oxygenases; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D000077591:Eucalyptol