Renal Toxicity and Carcinogenicity of Trichloroethylene: Key Results, Mechanisms, and Controversies

Brüning, Thomas; Bolt, Hermann M.

doi:10.1080/10408440091159202

Cited by 105 publications

(55 citation statements)

References 92 publications

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“…Thus, TCE exposure and metabolism yield several metabolites, including chloral, CH, dichloroacetic acid, trichloroacetic acid, trichloroethanol, and dichloroacetyl chloride. Although the assignment of a TCE metabolite to a specific toxic effect and/or to a specific tissue hast proven to be a complex issue, it has been proposed that trichloroacetic acid is associated with hepatotoxicity (Buben and O'Flaherty, 1985), trichloroacetic acid and dichloroacetic acid with hepatocarcinogenicity (Bull et al, 2002), and S-(1,2-dichlorovinyl)-L-cysteine with nephrotoxicity (Dekant et al, 1990;Bruning and Bolt, 2000).…”

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confidence: 99%

“…The conjugative pathway is a minor one and is associated with the nephrotoxic effects of TCE. Initial conjugation with glutathione, which takes place mainly in the liver, produces S- (1,2-dichlorovinyl)glutathione, and subsequent metabolic steps, including transport and biotransformation, result in the formation of S-(1,2-dichlorovinyl)-L-cysteine, a metabolite linked to nephrotoxicity in rats (Elfarra et al, 1986;Dekant et al, 1990;Bruning and Bolt, 2000). The major route of TCE metabolism in the liver is oxidation via the cytochrome P450 (P450) system, and P450 enzymes, including CYP2E1, CYP1A1/2, CYP2B1/2, and CYP2C11/6, have been implicated (Nakajima et al, 1990(Nakajima et al, , 1992aGuengerich et al, 1991).…”

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Pulmonary Bronchiolar Cytotoxicity and Formation of Dichloroacetyl Lysine Protein Adducts in Mice Treated with Trichloroethylene

Forkert

Millen²,

Lash³

et al. 2005

J Pharmacol Exp Ther

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This study was undertaken to test the hypothesis that bronchiolar damage induced by trichloroethylene (TCE) is associated with bioactivation within the Clara cells with the involvement of CYP2E1 and CYP2F2. Histopathology confirmed dose-dependent Clara cell injury and disintegration of the bronchiolar epithelium in CD-1 mice treated with TCE doses of 500 to 1000 mg/kg i.p. Immunohistochemical studies, using an antibody that recognizes dichloroacetyl lysine adducts, revealed dose-dependent formation of adducts in the bronchiolar epithelium. Localization of dichloroacetyl adducts in the Clara cells coincided with damage to this cell type in TCE-treated mice. Pretreatment of CD-1 mice with diallyl sulfone, an inhibitor of CYP2E1 and CYP2F2, abrogated the formation of the dichloroacetyl adducts and protected against TCE-induced bronchiolar cytotoxicity. Treatment of wild-type and CYP2E1-null mice with TCE (750 mg/kg i.p.) also elicited bronchiolar damage that correlated with the formation of adducts in the Clara cells. Immunoblotting, using lung microsomes from TCE-treated CD-1 mice, showed dose-dependent production of dichloroacetyl adducts that comigrated with CYP2E1 and CYP2F2. However, TCE treatment resulted in a loss of immunoreactive CYP2E1 and CYP2F2 proteins and p-nitrophenol hydroxylation, a catalytic activity associated with both cytochrome P450 enzymes. The TCE metabolite, chloral hydrate, was formed in incubations of TCE with lung microsomes from CD-1, wild-type, and CYP2E1-null mice. The levels were higher in CD-1 than in either wild-type or CYP2E1-null mice, although levels were higher in CYP2E1-null than in wild-type mice. These findings supported the contention that TCE bioactivation within the Clara cells, predominantly involving CYP2F2, correlated with bronchiolar cytotoxicity in mice.

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Pulmonary Bronchiolar Cytotoxicity and Formation of Dichloroacetyl Lysine Protein Adducts in Mice Treated with Trichloroethylene

Forkert

Millen²,

Lash³

et al. 2005

J Pharmacol Exp Ther

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“…[13][14][15][16] Prolonged exposure to trichloroethylene during metal machining is associated with clear-cell RCC harbouring a specific pattern of VHL somatic mutations; the identification of this putative mechanism increases the probability for a causative role of trichloroethylene in RCC. 12,17 We recently were made aware of an unexpected number of RCC occurring in a French factory that specialised in vitamin A, vitamin E and methionine synthesis. Between March 1994 and October 2002, 10 cases of RCC were detected in workers from this factory that currently employs 612 men and 116 women.…”

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High incidence of renal tumours in vitamins A and E synthesis workers: A new cause of occupational cancer?

Richard

Carrette

Béroud

et al. 2004

Intl Journal of Cancer

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Dear Sir,Renal cell carcinoma (RCC) is the most common adult kidney tumour, accounting for around 3% of human malignancies. 1 Its incidence is about 11/100,000 person-years in industrial countries and is increasing as the result of both increases in the prevalence of risk factors and in use of diagnostic imaging procedures. 2-3 Main histological subtypes include clear-cell (75%), papillary (10%) and chromophobe (5%) RCC. Complete surgical resection is considered to be curative for localised RCC but 30% of patients have metastatic disease at diagnosis and RCC is responsible for about 95,000 deaths per year world-wide. 1 Little is known regarding etiological factors of RCC. 2,4 Familial RCC syndromes are estimated at less than 5%; the 2 main conditions are von Hippel-Lindau disease, related to the tumour-suppressor VHL gene, for clear-cell RCC; and hereditary papillary RCC, caused by the c-MET proto-oncogene. 5 Most cases of RCC are thought to be sporadic and many factors are known to increase the risk. Tobacco smoking, obesity (particularly among women), high blood pressure and/or medication prescribed to treat this condition are the main established, although modest, risk factors. 6 -8 A number of reports have also pointed out the potential nephrocarcinogenic effect of occupational exposure to trichloroethylene, gasoline, petroleum products, asbestos, cadmium and iron processing fumes; corresponding epidemiological studies, however, are sometimes controversial. 9 -12 Somatic inactivation of the VHL gene is found in up to 70% of sporadic clear-cell RCC whereas somatic c-MET mutations only occur in 13% of papillary tumours. [13][14][15][16] Prolonged exposure to trichloroethylene during metal machining is associated with clear-cell RCC harbouring a specific pattern of VHL somatic mutations; the identification of this putative mechanism increases the probability for a causative role of trichloroethylene in RCC. 12,17 We recently were made aware of an unexpected number of RCC occurring in a French factory that specialised in vitamin A, vitamin E and methionine synthesis. Between March 1994 and October 2002, 10 cases of RCC were detected in workers from this factory that currently employs 612 men and 116 women. Because of the use of vinyl chloride, a well-documented liver carcinogen, an annual abdominal ultrasonography was progressively introduced in worker medical surveillance in the end of the 1980s. The first RCC was detected by chance in 1994 in a 48-year-old man, who had worked at vitamin A synthesis from 1979 to 1988. To date, 9 further men with RCC have been discovered through systematic ultrasonography and confirmed by CT-scan [ Table I]. Mean age at diagnosis was 52.3 Ϯ 7.8 years and mean diameter of tumour was 2.9 Ϯ 1.0 cm. All patients were successfully operated upon (6 patients underwent a nephrectomy and 4 were treated by conservative surgery) and were free of disease in March 2003. Review of tumour slides identified 7 clear-cell and 3 papillary RCC. The renal tumour was unique in 9 patients and multifoc...

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“…Although many cysteine S-conjugates appear to be nephrotoxic and even nephrocarcinogenic in humans (Chen et al, 1990;Birner et al, 1993Birner et al, , 1997Bruning and Bolt, 2000;Lash et al, 2000), the role of the human organic transporter 1 (hOAT1) in the transport of these substrates has been not shown. Although the negatively charged N-acetyl derivatives of DCVC (NAC-DCVC) and of CTFC (NAC-CTFC) have been shown to be substrates for rat Oat1 (Pombrio et al, 2001), the interaction of the parent zwitterionic cysteine conjugate DCVC or CTFC with OAT1 is not known.…”

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Interaction of Cysteine Conjugates with Human and Rabbit Organic Anion Transporter 1

Groves

Munoz

Bahn

et al. 2003

J Pharmacol Exp Ther

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Organic anion (OA) transport mediates accumulation of the zwitterionic nephrotoxic cysteine S-conjugates S-dichlorovinylcysteine (DCVC) and S-chlorotrifluoroethylcysteine (CTFC) in the rabbit renal proximal tubule (RPT). Although these cysteine conjugates are nephrotoxic to the human RPT, neither the role of OA transport nor the specific OA transport pathway(s) involved in cysteine conjugate accumulation are known. Since the OAT1 transporter has the characteristics of para-aminokippurate (PAH) transport that closely correlate to the native RPT, we examined the interaction of DCVC, CTFC, and the nontoxic benzothiazolylcysteine (BTC) with PAH transport mediated by human OAT1 and rabbit Oat1 expressed in Chinese hamster ovary and COS7 heterologous expression systems, respectively. Although the K m values for PAH uptake by hOAT1 and rbOat1 (8.9 Ϯ 3.6 and 20.7 Ϯ 8 M, respectively) were 5-to 10-fold less than the K m for peritubular PAH transport into rabbit RPT, the IC 50 values for DCVC, CTFC, and BTC inhibition of PAH uptake mediated by either hOAT1 or rbOat1 were similar between these two transporters and to the IC 50 values for these conjugates measured in rabbit RPT. The IC 50 for inhibition of hOAT1-and rbOat1-mediated PAH uptake by the hydrophobic conjugate BTC was more than 5-fold lower than the IC 50 values seen with DCVC and CTFC, suggesting that hydrophobicity increases the affinity of OAT1 for cysteine conjugates. Finally, preloading cells transfected with hOAT1 with BTC significantly trans-stimulated the uptake of PAH, consistent with the conclusion that BTC and, hence, other cysteine S-conjugates are substrates for hOAT1.

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Renal Toxicity and Carcinogenicity of Trichloroethylene: Key Results, Mechanisms, and Controversies

Cited by 105 publications

References 92 publications

Pulmonary Bronchiolar Cytotoxicity and Formation of Dichloroacetyl Lysine Protein Adducts in Mice Treated with Trichloroethylene

Pulmonary Bronchiolar Cytotoxicity and Formation of Dichloroacetyl Lysine Protein Adducts in Mice Treated with Trichloroethylene

High incidence of renal tumours in vitamins A and E synthesis workers: A new cause of occupational cancer?

Interaction of Cysteine Conjugates with Human and Rabbit Organic Anion Transporter 1

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