Molecular markers of trichloroethylene-induced toxicity in human kidney cells

• Published in: Toxicology and applied pharmacology Vol. 206; no. 2; pp. 157 - 168
• Main Authors: Lash, Lawrence H., Putt, David A., Hueni, Sarah E., Horwitz, Beth P.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 07.08.2005
• Subjects: 60 APPLIED LIFE SCIENCES; ANIMAL TISSUES; APOPTOSIS; Apoptosis - drug effects; BIOLOGICAL PATHWAYS; BIOLOGICAL STRESS; Biomarkers; CELL PROLIFERATION; Cell Proliferation - drug effects; Cells, Cultured; CLEAVAGE; CYSTEINE; Cysteine - analogs & derivatives; Cysteine - toxicity; DNA; EXTRAPOLATION; GLUTATHIONE; Human proximal tubular cells; Humans; IN VIVO; Kidney Tubules, Proximal - drug effects; Kidney Tubules, Proximal - pathology; METABOLISM; MICROTUBULES; Molecular markers; NECROSIS; Signal Transduction; Signaling pathways; TOXICITY; Trichloroethylene; Trichloroethylene - toxicity; TUBULES; Signaling pathways; Cell proliferation; Molecular markers; Trichloroethylene; Human kidney; Human proximal tubular cells; S-(1,2-Dichlorovinyl)- l-cysteine; Proximal tubular cells; Apoptosis
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2004.09.023

Difficulties in evaluation of trichloroethylene (TRI)-induced toxicity in humans and extrapolation of data from laboratory animals to humans are due to the existence of multiple target organs, multiple metabolic pathways, sex-, species-, and strain-dependent differences in both metabolism and susceptibility to toxicity, and the lack or minimal amount of human data for many target organs. The use of human tissue for mechanistic studies is thus distinctly advantageous. The kidneys are one target organ for TRI and metabolism by the glutathione (GSH) conjugation pathway is responsible for nephrotoxicity. The GSH conjugate is processed further to produce the cysteine conjugate, S-(1,2-dichlorovinyl)- l-cysteine (DCVC), which is the penultimate nephrotoxic species. Confluent, primary cultures of human proximal tubular (hPT) cells were used as the model system. Although cells in log-phase growth, which are undergoing more rapid DNA synthesis, would give lower LD 50 values, confluent cells more closely mimic the in vivo proximal tubule. DCVC caused cellular necrosis only at relatively high doses (>100 μM) and long incubation times (>24 h). In contrast, both apoptosis and enhanced cellular proliferation occurred at relatively low doses (10–100 μM) and early incubation times (2–8 h). These responses were associated with prominent changes in expression of several proteins that regulate apoptosis (Bcl-2, Bax, Apaf-1, Caspase-9 cleavage, PARP cleavage) and cellular growth, differentiation and stress response (p53, Hsp27, NF-κB). Effects on p53 and Hsp27 implicate function of protein kinase C, the mitogen activated protein kinase pathway, and the cytoskeleton. The precise pattern of expression of these and other proteins can thus serve as molecular markers for TRI exposure and effect in human kidney.