Protection by ginseng saponins against cyclophosphamide-induced liver injuries in rats by induction of cytochrome P450 expression and mediation of the l-arginine/nitric oxide pathway based on metabolomics

Ginseng saponins (GS) are the main active compounds in Panax ginseng and have been proven to be highly effective in attenuating the side effects of chemotherapy. However, there have been no reports on the mechanism of action of GS. Treatment with GS has certain benefits, including decreasing the toxicity levels in the liver [alanine aminotransferase (ALT), albumin (ALB), alkaline phosphatase (ALP), aspartate transaminase (AST)], reducing oxidative stress [malondialdehyde (MDA), nitric oxide (NO)], diminishing inflammatory factors [interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha) levels], and augmenting the levels of glutathione (GSH) and superoxide dismutase (SOD). The pharmacokinetics study showed that the area under the curve from 0 to 24 hr (AUC 0-24 hr) of 4-ketocyclophosphamide (4-KetoCTX) and carboxyphosphamide (CPM) was significantly increased after GS treatment. This study found that GS treatment can reduce chloroacetaldehyde (CAA) production by affecting CYP3A4, CYP2B6, and CYP2C9 protein expression in the liver. For the metabolomics study, GS attenuated the abnormalities of amino acid metabolic pathways in CP-induced liver injuries of rats and significantly enhanced the l-arginine level while reducing the serum nitric oxide (NO) level. This outcome was confirmed by the inhibition of the activities of NO synthase in the liver of rats.