Proteomics Analysis Reveals an Important Role for the PPAR Signaling Pathway in DBDCT-Induced Hepatotoxicity Mechanisms.

Yunlan Li,Xinxin Liu,Lin Niu,Qingshan Li

doi:10.3390/molecules22071113

Abstract

A patented organotin di-n-butyl-di-(4-chlorobenzohydroxamato)tin (DBDCT) with high a antitumor activity was designed, however, its antitumor and toxic mechanisms have not yet been clearly illustrated. Hepatic proteins of DBDCT-treated rats were identified and analyzed using LC-MS/MS with label-free quantitative technology. In total, 149 differentially expressed proteins were successfully identified. Five protein and mRNA expressions were involved in the peroxisome proliferator-activated receptor (PPAR) signaling pathway, including a scavenger receptor (CD36), adipocyte fatty acid binding protein 4 (FABP4), enoyl-CoA hydratase (EHHADH), acetyl-CoA acyltransferase 1 (ACAA1), and phosphoenolpyruvate carboxykinase (PEPCK) in DBDCT-treated Rat Liver (BRL) cells. PPAR-α and PPAR-λ were also significantly decreased at both protein and mRNA levels. Furthermore, compared with the DBDCT treatment group, a special blocking agent of PPAR-λ T0070907 was used to evaluate the relationship between PPAR-λ and its downstream genes. Our studies indicated that DBDCT may serve as a modulator of PPAR-λ, further up-regulating CD36, FABP4 and EHHADH on the PPAR signal pathway.

Highlights

Proteomics has been more frequently utilized as a new method to discuss the mechanism of anticancer activity, revealing the relationship between environment and health, and diagnosing and preventing disease [1,2,3,4]
Our studies indicated that DBDCT may serve as a modulator of peroxisome proliferator-activated receptor (PPAR)-λ, further up-regulating CD36, fatty acid binding protein 4 (FABP4) and EHHADH on the PPAR signal pathway
Focal fatty degeneration of hepatocyte was observed in the DBDCT-treated (5.0 mg/kg) rat livers

Summary

Introduction

Proteomics has been more frequently utilized as a new method to discuss the mechanism of anticancer activity, revealing the relationship between environment and health, and diagnosing and preventing disease [1,2,3,4]. Hep G2, SHSY5Y, HEC-1-B, EC, T24, HeLa and A549, along with human livers, HL-7702, and a normal human hepatocytes cell; the IC50 values were below 10 μM when tested cancer cell lines. It showed obvious antitumor activities in vivo against S180 and H22. DBDCT exhibited in vitro and in vivo antitumor activities, which, in some cases, were identical to, or even higher than, that of cisplatin, based on our former studies, it showed notable toxicity in many rat tissues, especially in the liver tissue. The acute toxicity tests indicated that acute necrosis, focal necrosis and Kupffer cells hyperplasia appeared in the DBDCT-treated rat livers [6].

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