Male reproductive toxicity and toxicokinetics of triptolide in rats.
As the unique quality control standard of Tabellae Glucosidorum Tripterygii Totorum, triptolide (CAS 38748-32-2) has a narrow therapeutic window. A significant side-effect of triptolide is its male reproductive toxicity the mechanism of which is still unknown. Therefore, in the present study the male reproductive toxicity and toxicokinetics of triptolide were investigated. Male Sprague-Dawley (SD) rats were treated with triptolide by oral administration (gastric infusion; 0, 100, 200, 400 microg/kg) once daily for 8 weeks. At the end of the treatment, the concentrations of triptolide in blood and testis samples were analyzed with liquid chromatography/mass spectrometry (LC/MS) to obtain the toxicokinetic parameters. Triptolide showed a non-linear kinetics profile and was rapidly absorbed but relatively slowly eliminated in the rats. Specifically, an accumulation of triptolide was seen in the testis. In the hematological study, mean corpuscular hemoglobin concentration (MCHC) had a marginal decrease in all triptolide treated groups. Alkaline phosphatase (ALP) in serum increased significantly only in the 400 microg/kg group during clinical chemistry assays although no histopathological change was found in the hematopoietic system or liver. In the male reproductive toxicity studies, the testis and epididymis weights of all triptolide treatment groups decreased significantly. The cauda epididymis sperm content and motility even decreased to zero. Evident changes were observed in the seminiferous tubules and the epididymides of triptolide treated rats (e.g., intraepithelial vacuoles of varying sizes; increased germ cells de generation, exfoliation and tubular atrophy). These findings provide valuable information to estimate the reproductive risk of triptolide in humans.
Ni
Bin
B
National Drug Screening Center, China Pharmaceutical University, Nanjing, The People's Republic of China.
Jiang
Zhenzhou
Z
Huang
Xin
X
Xu
Fengguo
F
Zhang
Rui
R
Zhang
Zunjian
Z
Tian
Yuan
Y
Wang
Tao
T
Zhu
Tian
T
Liu
Jing
J
Zhang
Luyong
L
D000818:Animals; D019540:Area Under Curve; D001772:Blood Cell Count; D001835:Body Weight / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D004224:Diterpenes / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity*; D004822:Epididymis / Q000166:cytology; D004852:Epoxy Compounds / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity; D006207:Half-Life; D007166:Immunosuppressive Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity*; D007248:Infertility, Male / Q000139:chemically induced*; D008297:Male; D013058:Mass Spectrometry; D009929:Organ Size / Q000187:drug effects; D010616:Phenanthrenes / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013076:Sperm Count; D013081:Sperm Motility / Q000187:drug effects; D013737:Testis / Q000378:metabolism
D004224:Diterpenes; D004852:Epoxy Compounds; D007166:Immunosuppressive Agents; D010616:Phenanthrenes; C001899:triptolide