The CYP2E1 inhibitor DDC up-regulates MMP-1 expression in hepatic stellate cells via an ERK1/2- and Akt-dependent mechanism

Tianhui Liu,Youqing Xu,Jidong Jia,Hong You,Ping Wang,Min Cong

doi:10.1042/bsr20130033

Tianhui Liu, Youqing Xu + Show 4 more

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https://doi.org/10.1042/bsr20130033

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Journal: Bioscience reports	Publication Date: Jun 1, 2013
Citations: 18	License type: CC BY 3.0

Affiliation: Beijing Friendship Hospital

Abstract

DDC (diethyldithiocarbamate) could block collagen synthesis in HSC (hepatic stellate cells) through the inhibition of ROS (reactive oxygen species) derived from hepatocyte CYP2E1 (cytochrome P450 2E1). However, the effect of DDC on MMP-1 (matrix metalloproteinase-1), which is the main collagen degrading matrix metalloproteinase, has not been reported. In co-culture experiments, we found that DDC significantly enhanced MMP-1 expression in human HSC (LX-2) that were cultured with hepatocyte C3A cells either expressing or not expressing CYP2E1. The levels of both proenzyme and active MMP-1 enzyme were up-regulated in LX-2 cells, accompanied by elevated enzyme activity of MMP-1 and decreased collagen I, in both LX-2 cells and the culture medium. H2O2 treatment abrogated DDC-induced MMP-1 up-regulation and collagen I decrease, while catalase treatment slightly up-regulated MMP-1 expression. These data suggested that the decrease in ROS by DDC was partially responsible for the MMP-1 up-regulation. ERK1/2 (extracellular signal-regulated kinase 1/2), Akt (protein kinase B) and p38 were significantly activated by DDC. The ERK1/2 inhibitor (U0126) and Akt inhibitor (T3830) abrogated the DDC-induced MMP-1 up-regulation. In addition, a p38 inhibitor (SB203580) improved MMP-1 up-regulation through the stimulation of ERK1/2. Our data indicate that DDC significantly up-regulates the expression of MMP-1 in LX-2 cells which results in greater MMP-1 enzyme activity and decreased collagen I. The enhancement of MMP-1 expression by DDC was associated with H2O2 inhibition and coordinated regulation by the ERK1/2 and Akt pathways. These data provide some new insights into treatment strategies for hepatic fibrosis.

Highlights

DDC and its derivatives are widely used in clinical applications
DDC up-regulates matrix metalloproteinase-1 (MMP-1) through activating ERK1/2 and protein kinase B (Akt) After demonstrating that Akt, ERK1/2 and p38 may contribute to DDC-induced MMP-1 up-regulation, we examined the effect of DDC on ERK1/2, p38 and Akt activity
To determine if similar mechanisms were involved in LX-2 cells co-cultured with C3A cells, we investigated the effect of DDC on the activation of ERK1/2, p38 and Akt in LX-2 cells co-cultured with C3A cells

Summary

Introduction

DDC (diethyldithocarbamate) and its derivatives are widely used in clinical applications. DDC can act as a radioprotective agent and its derivative, disulfiram, is used clinically to treat alcoholism because of its ability to inhibit ALDH (aldehyde dehydrogenase) [1,2]. It has been reported that low doses of DDC protect against liver injury induced by many hepatotoxic agents via inhibitory activity on drug metabolizing enzymes and antioxidant effects in rats [3]. DDC or disulfiram (pro-drug of DDC) is widely used for inhibition of CYP2E1 (cytochrome P450 2E1) in human studies because of its selectivity and relative lack of toxicity [4]. Hepatic CYP2E1 has been linked to the pathogenesis of ASH (alcoholic steatohepatitis) [7], hepatic steatosis and NASH (non-alcoholic steatohepatitis) [8,9,10].

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