Ferric nitrilotriacetate (
Fe-NTA) is a potent nephrotoxicant and a renal
carcinogen that induces its effect by causing oxidative stress. The present study was undertaken to explore protective effect of
silymarin, a flavonolignan from milk thistle (Silybum marianum), against
Fe-NTA mediated renal oxidative stress,
inflammation and
tumor promotion response along with elucidation of the implicated mechanism(s). Administration of
Fe-NTA (10 mg/kg bd wt, i.p.) to Swiss albino mice induced marked oxidative stress in kidney, evident from augmentation in renal
metallothionein (MT) expression, depletion of
glutathione content and activities of
antioxidant and phase II metabolizing
enzymes, and enhancement in production of
aldehyde products such as
4-hydroxy-2-nonenal.
Fe-NTA also significantly activated
nuclear factor kappa B (NFkappaB) and upregulated the expression of downstream genes:
cyclooxygenase 2 and
inducible nitric oxide synthase and enhancing the production of proinflammatory
cytokines:
tumor necrosis factor alpha (
TNF-alpha) and
interleukin-6 (IL-6). However, feeding of 0.5% and 1%
silymarin diet conferred a significant protection against
Fe-NTA induced oxidative stress and
inflammation. It further augmented MT expression, restored the
antioxidant armory, ameliorated NFkappaB activation and decreased the expression of proinflammatory mediators.
Silymarin also suppressed
Fe-NTA induced hyperproliferation in kidney, ameliorating renal
ornithine decarboxylase activity and
DNA synthesis. From these results, it could be concluded that
silymarin markedly protects against chemically induced
renal cancer and acts plausibly by virtue of its
antioxidant, anti-inflammatory and antiproliferative activities.