Role of mitochondrial dysfunction in cellular responses to S-(1,2-dichlorovinyl)-l-cysteine in primary cultures of human proximal tubular cells

Abstract

The nephrotoxic metabolite of the environmental contaminant trichloroethylene, S-(1,2-dichlorovinyl)-L-cysteine (DCVC), is known to elicit cytotoxicity in rat and human proximal tubular (rPT and hPT, respectively) cells that involves inhibition of mitochondrial function. DCVC produces a range of cytotoxic and compensatory responses in hPT cells, depending on dose and exposure time, including necrosis, apoptosis, repair, and enhanced cell proliferation. The present study tested the hypothesis that induction of mitochondrial dysfunction is an obligatory step in the cytotoxicity caused by DCVC in primary cultures of hPT cells. DCVC-induced necrosis was primarily a highconcentration (≥ 50 μM) and lat (≥ 24 hr) response whereas apoptosis and increased proliferation occurred at relatively low concentrations (< 50 μM) and early time points (≤ 24 hr). Decreases in cellular DNA content, indicative of cell loss, were observed at DCVC concentrations as low as 1 μM. Involvement of mitochondrial dysfunction in DCVC-induced cytotoxicity was supported by showing that DCVC caused modest depletion of cellular ATP, inhibition of respiration, and activation of caspase-3/7. Cyclosporin A protected cells against DCVC-induced apoptosis and both cyclosporin A and ruthenium red protected cells against DCVC-induced loss of mitochondrial membrane potential. DCVC caused little or no activation of caspase-8 and did not significantly induce expression of Fas receptor, consistent with apoptosis occurring only by the mitochondrial pathway. These results support the conclusion that mitochondrial dysfunction is an early and obligatory step in DCVC-induced cytotoxicity in hPT cells.

Hesperidin ameliorates trichloroethylene-induced nephrotoxicity by abrogation of oxidative stress and apoptosis in wistar rats

“…Our results of immunohistochemistry showed that hesperidin alleviates the effect of TCE-induced nephrotoxicity. Expression of caspase-3 was assessed and was found to be elevated in the TCEtreated group compared to the control group, signifying that TCE activates caspase-3, thus, in agreement with earlier reports [65]. Treatment with hesperidin showed reduced caspase-3 expression in the low dose group, which was further downregulated and was found to be almost similar to the control group with high-dose hesperidin pretreatment.…”

The trichloroethylene metabolite S-(1,2-dichlorovinyl)-l-cysteine but not trichloroacetate inhibits pathogen-stimulated TNF-α in human extraplacental membranes in vitro

“…The effective DCVC concentrations for inhibition of LTA, LPS, and GBS stimulation of TNF-α release in the present study were at or near the lowest bioactive concentrations of DCVC reported in kidney cells [57]. The relevance of concentrations of DCVC to human exposure is difficult to establish due to insufficient data [15].…”

Localization of the trichloroethylene-related compound <i>S</i>-(1, 2-dichlorovinyl)-<i>L</i>-cysteine in mouse cartilage

“…DCVC is considered to cause renal cell injury after metabolic activation by cysteine conjugate β-lyase (Cummings and Lash, 2000;Tateishi et al, 1978;Tomisawa et al, 1986). Current understanding of the mechanism of DCVC-induced renal injury derives primarily from studies on isolated proximal tubular cells (Cummings and Lash, 2000;Lash et al, 2014;Xu et al, 2008) or subcellular fractions of renal cortical homogenates from rats, rabbits, and other non-human mammals (Davis and Petry, 1994;Lash et al, 2001;Wolfgang et al, 1990). We also reported subchronic nephrotoxic effects of DCVC in mice (Shirai et al, 2012).…”