Reported
as two antirenal cell carcinoma (RCC) drug candidates,
marine-derived compounds piericidin A (PA) and glucopiericidin A (GPA)
exhibit hepatotoxicity in renal carcinoma xenograft mice. Proteomics
and transcriptomics reveal the hepatotoxicity related with cholesterol
disposition since RCC is characterized by cholesterol accumulation.
PA/GPA aggravate hepatotoxicity in high-cholesterol diet (HCD)-fed
mice while exhibiting no toxicity in chow diet-fed mice. High cholesterol
accumulation in liver is liver X receptor (LXR)-mediated cytochrome
P450 family 7 subfamily a member 1 (CYP7A1) depression and low-density
lipoprotein receptor (LDLR) activation. The farnesoid X nuclear receptor
(FXR) is also depressed with a downregulated target gene OSTα. Different from PA directly combined with LXRα as an inhibitor,
GPA exists as a prodrug in the liver and exerts toxic effects due
to transformation into PA. Surface plasmon resonance (SPR) and docking
results of 17 piericidins illustrate that glycosides exert no LXRα
binding activity. A longer survival time of GPA-treated mice indicates
that further exploration in anti-RCC drug research should focus on
reducing glycosides transformed into PA and concentrating in the kidney
tumor rather than the liver for lowering the risk of hepatotoxicity.