Acute nephrotoxicity of aristolochic acids in mice.
Aristolochic acids (AA), present in Aristolochia plants, are the toxin responsible for Chinese herbs nephropathy (CHN), a rapidly progressive tubulointerstitial nephritis (TIN). To clarify the mechanisms of the development of CHN, we tried to induce TIN in mice using AA. Three strains of inbred mice, BALB/c, C3H/He and C57BL/6, received 2.5 mg kg(-1) of AA or AA sodium salt (AANa) daily by intraperitoneal or oral administration, 5 days a week for 2 weeks. Serum and renal tissue were obtained at sacrifice. Twelve-hour urine samples were individually collected in a metabolic cage at one-week intervals. In the AA-injected groups, severe tubular injury, with the appearance of acute tubular necrosis, and rare cell infiltration into the interstitium, were seen in BALB/c mice. C3H/He mice also developed TIN with prominent cell infiltration into the interstitium and interstitial fibrosis. In C57BL/6 mice, only mild and focal tubulointerstitial changes were seen. Serum creatinine and blood urea nitrogen increased in BALB/c and C3H/He mice. Immunofluorescent study revealed no deposition of immune components in kidneys. In the AANa-treated groups, TIN was also seen in all groups, but even more severe tubulointerstitial changes were induced by intraperitoneal injection. Further examination using purified AAI, AAII, AAIVa and aristolactam I (ALI) revealed that AAI induced strong nephrotoxicity in mice, and that AAII resulted in mild nephrotoxicity. However, AAIVa and ALI caused no nephrotoxicity in this experimental system. There are strain differences in mice in their susceptibility to AA nephropathy. AAI exerted the strongest nephrotoxic effect in mice.
Sato
Noriko
N
Department of Drug Information and Communication, Graduate School of Pharmaceutical Sciences, Chiba University, 1-33, Yayoi-cho, Inage-ku, Chiba 263-8522, Japan. nori@p.chiba-u.ac.jp
Takahashi
Daisuke
D
Chen
Shih-Ming
SM
Tsuchiya
Reiko
R
Mukoyama
Takuya
T
Yamagata
Shin-ichi
S
Ogawa
Makoto
M
Yoshida
Masaaki
M
Kondo
Seizo
S
Satoh
Nobunori
N
Ueda
Shiro
S
D000208:Acute Disease; D000284:Administration, Oral; D000818:Animals; D030022:Aristolochia; D034341:Aristolochic Acids / Q000009:adverse effects*; D001806:Blood Urea Nitrogen; D001835:Body Weight / Q000187:drug effects; D003404:Creatinine / Q000097:blood; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D004365:Drugs, Chinese Herbal / Q000008:administration & dosage / Q000009:adverse effects / Q000737:chemistry; D007267:Injections; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D009395:Nephritis, Interstitial / Q000139:chemically induced* / Q000473:pathology*; D008517:Phytotherapy; D018517:Plant Roots / Q000737:chemistry; D010946:Plants, Medicinal / Q000009:adverse effects
D034341:Aristolochic Acids; D004365:Drugs, Chinese Herbal; C121135:aristolactam I; D003404:Creatinine