title: Inhibition of renal NQO1 activity by dicoumarol suppresses nitroreduction of aristolochic acid I and attenuates its nephrotoxicity.
abstract: Aristolochic acid I (AAI) is the major toxic component of aristolochic acid that causes aristolochic acid nephropathy and Balkan endemic nephropathy. Nitroreduction is an essential metabolic process for AAI rapid clearance in different species including humans. However, which enzyme participates in AAI nitroreduction in vivo and whether this metabolic process contributes to AAI nephrotoxicity are unclear. Here, we showed that NAD(P)H:quinone oxidoreductase 1 (NQO1) was highly expressed in mouse renal tubular epithelial cells. Inhibition of NQO1 activity by dicoumarol pretreatment significantly decreased renal aristolactam I (ALI) levels, a major reductive metabolite of AAI, whereas it increased renal AAI and its major oxidative metabolite 8-hydroxy-aristolochic acid I (AAIa) levels in male C57BL/6 mice. Similar changes in renal ALI, AAI, and AAIa levels were also observed in mice pretreated with another NQO1 inhibitor, phenindione. Consistent with higher levels of renal AAI and AAIa found in dicoumarol-pretreated mice, their serum clearance was much slower compared with vehicle-pretreated mice. The survival rate of mice pretreated with dicoumarol was markedly increased when higher doses of AAI were given. Similarly, pretreatment of mice with phenindione also attenuated AAI-induced nephrotoxicity. These results indicate that NQO1 plays an important role in renal AAI nitroreduction and may thus contribute to AAI-induced nephrotoxicity.
authors: Center for Drug Safety Evaluation and Research, State Key Laboratory of New Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Pudong, Shanghai 201203, China.
authors: Min
authors: M
authors: Chen
authors: Likun
authors: L
authors: Gong
authors: Xinming
authors: X
authors: Qi
authors: Guozhen
authors: G
authors: Xing
authors: Yang
authors: Y
authors: Luan
authors: Yuanfeng
authors: Y
authors: Wu
authors: Ying
authors: Y
authors: Xiao
authors: Jun
authors: J
authors: Yao
authors: Yan
authors: Y
authors: Li
authors: Xiang
authors: X
authors: Xue
authors: Guoyu
authors: G
authors: Pan
authors: Jin
authors: J
authors: Ren