The role of organic anion transport peptides in cyclophosphamide-induced hepatotoxicity in high-fat diet mice.

Clinically, patients with lipid metabolism disorders caused by factors such as high-fat diet (HFD) developed severer liver damage and lipid metabolism disorders after treatment with cyclophosphamide (CTX). This can lead to elevated levels of inflammatory cytokines, which in turn lead to changes in levels of various liver and kidney transporters, to increase drug accumulation, which may be a way to exacerbate liver injury. The role of organic anion transport peptides (OATPs), an important uptake transporter, in the transport process of CTX and in the aggravation of liver injury induced by CTX in HFD mice is unclear. The aim of this study was to characterize the hepatotoxicity and lipid metabolism disorders of HFD mice exposed to CTX and to investigate the possible mechanism from the perspective of drug in vivo process and transporter regulation. It has been verified that CTX induced severer liver injury in HFD mice compared with the control group, accompanied with upregulated Interleukin-1β (IL-1β) expression and down-regulated OATPs expression in liver and renal, and increased blood CTX concentration. This suggested that the down-regulation of OATPs involved in IL-1β may play an important role in HFD-CTX-induced liver injury, and then experiments in Hep G2 cells was used to validate the hypothesis. Pharmacokinetic and primary hepatocyte uptake experiments confirmed that OATPs may be an important factor involved in the in vivo process of CTX. In summary, this study demonstrated that HFD mice exhibited severer liver toxicity after exposure to CTX, which may be caused by the disorder of lipid levels and the up-regulation of inflammatory factors, and then the downregulation of liver and renal OATPs to increase the accumulation of CTX in vivo. These findings suggest that IL-1β and OATPs may be involved in the interactive regulation of CTX accumulation and endogenous lipid disturbance, and play very important role in the aggravation of liver injury induced by CTX in HFD mice.