Effects of cytochrome P4503A inducer dexamethasone on the metabolism and toxicity of triptolide in rat.
Triptolide (TP), a major active and toxic component of Tripterygium wilfordii, is reported to be converted into four mono-hydroxylated metabolites (m/z 375) by cytochrome P450 (CYP) in vitro, and CYP3A4 was the primary isoform responsible for its hydroxylation. Dexamethasone (DXM), a CYP3A inducer, is frequently combined with TP in clinical therapy. However, the effects of DXM on the metabolism and toxicity of TP are unknown. In this study, the metabolism of TP was investigated in rat liver microsomes pretreated with DXM. The metabolic profile of TP was significantly altered. The V(max) was about 9.58-fold higher than that of vehicle group and the K(m) was about 3.57-fold higher. With DXM, the amount of metabolite M3 was significantly higher than that with no DXM while M1 and M2 were not found, and a new metabolite (m/z 391) was observed. The liver and the kidney toxicity of TP on rat pretreated with DXM were evaluated. We observed that pretreatment with DXM protected against TP hepatotoxicity. No obvious nephrotoxicity was detected on rats treated with TP, whereas the kidney damage was observed in DXM group and the level of toxicity was much reduced with DXM-TP group. This suggested that TP might decrease nephrotoxicity induced by DXM. These studies indicated that DXM had significant impact on the metabolism and the toxicity of TP as a therapeutic agent.
Ye
Xiaochuan
X
Institute of Materia Medica, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China.
Li
Wenyuan
W
Yan
Yan
Y
Mao
Chengwen
C
Cai
Ruxiu
R
Xu
Huibi
H
Yang
Xiangliang
X
D000818:Animals; D015415:Biomarkers / Q000097:blood; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003907:Dexamethasone / Q000737:chemistry / Q000494:pharmacology*; D004224:Diterpenes / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D004852:Epoxy Compounds / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D010616:Phenanthrenes / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D013438:Sulfhydryl Compounds / Q000378:metabolism
D015415:Biomarkers; D004224:Diterpenes; D004852:Epoxy Compounds; D010616:Phenanthrenes; D013438:Sulfhydryl Compounds; C001899:triptolide; D003907:Dexamethasone; D003577:Cytochrome P-450 Enzyme System; C465260:Cyp3a2 protein, rat; D051544:Cytochrome P-450 CYP3A