Hepatic cytochrome P450s metabolize aristolochic acid and reduce its kidney toxicity.
Cytochrome P450s metabolize the naturally occurring nephrotoxin aristolochic acid. Using liver-specific cytochrome P450 reductase-null mice we found that a low but lethal dose of aristolochic acid I was ineffective in wild-type mice. Induction of hepatic CYP1A by 3-methylcholanthrene pretreatment markedly increased the survival rate of wild type mice given higher doses and these mice were protected from aristolochic acid I-induced renal injury. Clearance of aristolochic acid I in null mice was slower compared to control and the 3-methylcholanthrene-pretreated wild type mice. The levels of aristolochic acid I in the kidney and liver were much higher in null mice but much lower in 3-methylcholanthrene-treated compared to control wild type mice. Hepatic microsomes from 3-methylcholanthrene-treated wild type mice had greater activity compared to untreated mice. Finally, aristolochic acid I was more cytotoxic than its major metabolite aristolactam I and this cytotoxicity was decreased in human renal tubular epithelial HK2 cells in the presence of a reconstituted hepatic microsome-cytosol (S9) system. These results indicate that hepatic P450s play an important role in metabolizing aristolochic acid I into less toxic metabolites and thus have a detoxification role in aristolochic acid I-induced kidney injury.
Xiao
Y
Y
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
Ge
M
M
Xue
X
X
Wang
C
C
Wang
H
H
Wu
X
X
Li
L
L
Liu
L
L
Qi
X
X
Zhang
Y
Y
Li
Y
Y
Luo
H
H
Xie
T
T
Gu
J
J
Ren
J
J
D000818:Animals; D034341:Aristolochic Acids / Q000378:metabolism* / Q000633:toxicity; D002273:Carcinogens / Q000378:metabolism* / Q000633:toxicity; D002458:Cell Fractionation; D008658:Inactivation, Metabolic; D007674:Kidney Diseases / Q000139:chemically induced* / Q000201:enzymology* / Q000473:pathology; D008099:Liver / Q000201:enzymology*; D008297:Male; D008748:Methylcholanthrene / Q000633:toxicity; D051379:Mice; D008817:Mice, Mutant Strains; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D009251:NADPH-Ferrihemoprotein Reductase / Q000235:genetics / Q000378:metabolism*
D034341:Aristolochic Acids; D002273:Carcinogens; D008748:Methylcholanthrene; C000228:aristolochic acid I; D009251:NADPH-Ferrihemoprotein Reductase