Sex differences in subacute toxicity and hepatic microsomal metabolism of triptolide in rats.
Triptolide, a major active component of Tripterygium wilfordii Hook F (TWHF), has multiple pharmacological activities. However, its clinical use is often limited by its severe toxicity. In the present study, we evaluated the oral toxicity of triptolide in Sprague-Dawley rats for 28 days at the dosages of 0, 200 and 400microg/kg/day, respectively. Significant difference in the toxicity of triptolide at 400microg/kg was found between different sexes. The triptolide-treated female rats showed many abnormalities, including anorexia, diarrhea, leanness, suppression of weight gain and food intake, fatty liver, splenomegaly and atrophy of ovaries. In contrast, no such abnormalities were observed in male rats except for the significant reproductive toxicity. Furthermore, the metabolism of triptolide in liver microsomes from both sexes was investigated by HPLC. A greater rate of triptolide metabolism was observed in male rat hepatic microsomes, suggesting that one of the cytochrome P450s (CYPs) responsible for triptolide metabolism is male-specific or predominant at least. The inhibition experiments with CYP inhibitors showed that CYP3A and CYP2B were mainly involved in the metabolism of triptolide. In addition, since CYP3A2 is a male-predominant form in rats, significant sex difference in the metabolism of triptolide disappeared in vitro after anti-rat CYP3A2 antibody pretreatment. Results suggested that CYP3A2 made an important contribution to the sex-related metabolism of triptolide, which may result in the sex differences in triptolide toxicity.
Liu
Li
L
Jiangsu Center of Drug Screening, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210038, China; Department of Pharmacology, School of Medicine, Yangzhou University, Yangzhou 225001, China.
Jiang
Zhenzhou
Z
Liu
Jing
J
Huang
Xin
X
Wang
Tao
T
Liu
Jun
J
Zhang
Yun
Y
Zhou
Zhixing
Z
Guo
Jianlu
J
Yang
Lina
L
Chen
Yun
Y
Zhang
Luyong
L
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors / Q000378:metabolism; D019362:Cytochrome P-450 CYP2B1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A; D003907:Dexamethasone / Q000494:pharmacology; D004224:Diterpenes / Q000378:metabolism* / Q000633:toxicity*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004852:Epoxy Compounds / Q000378:metabolism / Q000633:toxicity; D005260:Female; D007654:Ketoconazole / Q000494:pharmacology; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D010616:Phenanthrenes / Q000378:metabolism* / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012737:Sex Factors
D004224:Diterpenes; D004791:Enzyme Inhibitors; D004852:Epoxy Compounds; D008565:Membrane Proteins; D010616:Phenanthrenes; C001899:triptolide; D003907:Dexamethasone; D001189:Aryl Hydrocarbon Hydroxylases; C465260:Cyp3a2 protein, rat; D019362:Cytochrome P-450 CYP2B1; D051544:Cytochrome P-450 CYP3A; D007654:Ketoconazole