β-lapachone protects against doxorubicin-induced hepatotoxicity through modulation of NAD+ /SIRT-1/FXR/p-AMPK/NF-kB and Nrf2 signaling axis.

Abstract

Doxorubicin (DOX)is a widely used antineoplastic drug, but its clinical use is limited by significant toxicities, such as hepatotoxicity. In this study, we evaluated the effects of β-lapachone (β-LAP),a natural quinone-containing compound, in a mouse model of DOX-induced hepatotoxicity. β-LAPwas orally administered at 1.25, 2.5, and 5 mg/kg for 4 days, and a single dose of DOX (20 mg/kg) was injected intraperitoneally on the second day. Histopathological changes, liver function markers, antioxidant and inflammatory markers were assessed. β-LAPameliorated liver injury and liver function markers evoked by DOX. β-LAP also downregulated the mRNA expression of nuclear factor-kB-corresponding genes including interleukin-6, interleukin-1β, and tumor necrosis factor-α. Moreover, β-LAPincreased the nuclear factor erythroid 2-related factor 2 target genes heme oxygenase-1 and NAD(P)H: quinone oxidoreductase 1, along with antioxidant enzymes including reduced glutathione, catalase, and superoxide dismutase with simultaneous reduction in the lipid peroxidation product malondialdehyde. Meanwhile, it recovered NAD+ /NADH ratios and subsequently elevated the protein levels of sirtuin-1 (SIRT-1),farnesoid X receptor (FXR),and phosphorylated AMP-activated protein kinase (p-AMPK).Collectively, these findings suggest a protective role of β-LAPagainst DOX-induced hepatotoxicity by partly regulating the NAD+ /SIRT-1/FXR/p-AMPKaxis.