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Hypersensitivity to Cisplatin and Gentamycin Induced Nephrotoxicity in Mice with Decreased Expression of NADPH‐Cytochrome P450 Reductase

Cytochrome P450 reductase (CPR or POR) is an obligatory redox partner for all microsomal P450 enzymes. A large, global decrease in POR expression, in a Cpr‐low mouse model, was previously found to lead to altered sex steroid hormone homeostasis, female infertility, and decreased capacity for xenobiotic metabolism. The aim of this study was to further characterize the Cpr‐low mouse model, in order to identify additional phenotypes that may reveal vulnerability in people with low POR expression. Here, we report differences between wild‐type and Cpr‐low mice in their sensitivities to drug‐induced toxicity in the renal proximal tubules. We studied two drugs, the anticancer drug cisplatin and the antibiotic drug gentamycin, which are known as renal toxicants, but are not P450 substrates. Toxicity was assessed by blood urea nitrogen (BUN) levels and histopathology of the kidney. At drug doses that do not cause renal toxicity in wild‐type mice, cisplatin caused significant increases in BUN levels over vehicle control group in both male and female Cpr‐low mice, whereas gentamycin caused significant increases in BUN levels over vehicle control group in male but not female Cpr‐low mice. Corresponding histopathological changes, including appearance of extensive proximal tubule vacuolization, were found in the kidneys of drug‐treated Cpr‐low mice. These findings suggest that POR expression level could be a risk factor for drug‐induced nephrotoxicity in patients.