Metabolism and Tissue Distribution of Orally Administered Trichloroethylene in Male and Female Rats: Identification of Glutathione- and Cytochrome P-450-Derived Metabolites in Liver, Kidney, Blood, and Urine

Lash, Lawrence H.; Putt, David A.; Parker, Jean C.

doi:10.1080/15287390500360133

Cited by 44 publications

(39 citation statements)

References 45 publications

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“…Maximal rates of TCE oxidative metabolism in rodents also differ between males and females. For example, Lash et al [53] found higher concentrations of CYP-derived metabolites of TCE ( i.e ., CH, TCA, TCOH) in livers of males than in females; the opposite pattern, however, was observed in kidneys. These results are consistent with higher maximal rates of CYP-dependent metabolism and overall metabolic clearance of TCE in male rats.…”

Section: Cyp-dependent Oxidation Of Tcementioning

confidence: 99%

Trichloroethylene biotransformation and its role in mutagenicity, carcinogenicity and target organ toxicity

Lash

Chiu²,

Guyton

et al. 2014

Mutation Research/Reviews in Mutation Research

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Metabolism is critical for the mutagenicity, carcinogenicity, and other adverse health effects of trichloroethylene (TCE). Despite the relatively small size and simple chemical structure of TCE, its metabolism is quite complex, yielding multiple intermediates and end-products. Experimental animal and human data indicate that TCE metabolism occurs through two major pathways: cytochrome P450 (CYP)-dependent oxidation and glutathione (GSH) conjugation catalyzed by GSH S-transferases (GSTs). Herein we review recent data characterizing TCE processing and flux through these pathways. We describe the catalytic enzymes, their regulation and tissue localization, as well as the evidence for transport and inter-organ processing of metabolites. We address the chemical reactivity of TCE metabolites, highlighting data on mutagenicity of these end-products. Identification in urine of key metabolites, particularly trichloroacetate (TCA), dichloroacetate (DCA), trichloroethanol and its glucuronide (TCOH and TCOG), and N-acetyl-S-(1,2-dichlorovinyl)-L-cysteine (NAcDCVC), in exposed humans and other species (mostly rats and mice) demonstrates function of the two metabolic pathways in vivo. The CYP pathway primarily yields chemically stable end-products. However, the GST pathway conjugate S-(1,2-dichlorovinyl)glutathione (DCVG) is further processed to multiple highly reactive species that are known to be mutagenic, especially in kidney where in situ metabolism occurs. TCE metabolism is highly variable across sexes, species, tissues and individuals. Genetic polymorphisms in several of the key enzymes metabolizing TCE and its intermediates contribute to variability in metabolic profiles and rates. In all, the evidence characterizing the complex metabolism of TCE can inform predictions of adverse responses including mutagenesis, carcinogenesis, and acute and chronic organ-specific toxicity.

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Section: Cyp-dependent Oxidation Of Tcementioning

confidence: 99%

Trichloroethylene biotransformation and its role in mutagenicity, carcinogenicity and target organ toxicity

Lash

Chiu²,

Guyton

et al. 2014

Mutation Research/Reviews in Mutation Research

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“…Humans exposed to relatively low levels of TRI by inhalation (i.e., 100 ppm) transiently exhibit as high as 50 μM concentrations of the GSH conjugate of TRI, S-(1,2-dichlorovinyl)glutathione (DCVG), in the plasma [35] and rats exposed to TRI by oral gavage exhibit renal cortical concentrations of DCVC as high as 50 pmol/g tissue [36]. These data suggest that under typical environmental exposure conditions (< 5 ppb), even the lowest concentration of DCVC that was tested (i.e., 1 μM) would be high.…”

Section: Experimental Designmentioning

confidence: 99%

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

Papanayotou

Putt

et al. 2008

Biochemical Pharmacology

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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.

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“…However, NA-DCVC can be deacetylated by AA3-which is highly expressed in the renal proximal tubule, liver, and brain-to generate S-1,2-dichlorovinyl-L-cysteine (DCVC) (2) and further transformed via β-lyases or flavin monooxygenases into lethal products capable of causing acute renal failure and toxicity to the liver and brain. (4,(13)(14)(15)(16)(17)(18)(19)(20)(21)(22). Thus, inhibition of AA3 can decrease DCVC formation and ameliorate TCE toxicity, presenting a potential target for drug discovery.…”

mentioning

confidence: 99%

Structures of aminoacylase 3 in complex with acetylated substrates

Hsieh

Tsirulnikov²,

Sawaya³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Trichloroethylene (TCE) is one of the most widespread environmental contaminants, which is metabolized to N-acetyl-S-1,2-dichlorovinyl-L-cysteine (NA-DCVC) before being excreted in the urine. Alternatively, NA-DCVC can be deacetylated by aminoacylase 3 (AA3), an enzyme that is highly expressed in the kidney, liver, and brain. NA-DCVC deacetylation initiates the transformation into toxic products that ultimately causes acute renal failure. AA3 inhibition is therefore a target of interest to prevent TCE induced nephrotoxicity. Here we report the crystal structure of recombinant mouse AA3 (mAA3) in the presence of its acetate byproduct and two substrates: N α -acetyl-L-tyrosine and NA-DCVC. These structures, in conjunction with biochemical data, indicated that AA3 mediates substrate specificity through van der Waals interactions providing a dynamic interaction interface, which facilitates a diverse range of substrates.mercapturates | metalloprotein | X-ray structure A minoacylase 3 (AA3) is a member of the aminoacylase family of enzymes that deacylates a broad range of substrates including both N α -acetylated amino acids and S-cysteine conjugates of N-acetyl-L-cysteine (mercapturic acids) ( Fig. 1) (1). There are three types of aminoacylases: (i) aminoacylase 1 (AA1) deacetylates neutral aliphatic N-acyl-α-amino acids and mercapturic acids; (ii) aminoacylase 2 or aspartoacylase (AA2) has a strict specificity for N α -acetyl-L-aspartate (NAD); and (iii) aminoacylase 3 (AA3) preferentially deacetylates N α -acetylated aromatic amino acids and mercapturic acids that are usually not deacetylated by AA1 (1-6). Despite different substrate specificities, AA2 and AA3 have a high degree of sequence (42% identity) and structure homology but are both substantially different from AA1 (∼10% of sequence identity) (2, 6-10).AA3 is of particular interest for human health because it participates in mediating toxicity of the xenobiotic trichloroethylene (TCE). The United States produces in excess of 130,000 tons of TCE per year (11), making it the most widespread chemical contaminant in both soil and ground water. TCE is readily absorbed into the body where it can enter the glutathione conjugation detoxification pathway producing the mercapturic acid N-acetyl-S-1,2-dichlorovinyl-L-cysteine (NA-DCVC) for subsequent urinary excretion (12, 13). However, NA-DCVC can be deacetylated by AA3-which is highly expressed in the renal proximal tubule, liver, and brain-to generate S-1,2-dichlorovinyl-L-cysteine (DCVC) (2) and further transformed via β-lyases or flavin monooxygenases into lethal products capable of causing acute renal failure and toxicity to the liver and brain. (4, 13-22). Thus, inhibition of AA3 can decrease DCVC formation and ameliorate TCE toxicity, presenting a potential target for drug discovery.Generating specific inhibitors for AA3 would be greatly aided by high-resolution structural data, but structural studies of aminoacylases have been limited to AA1 (7) and AA2 (8, 9), which differ in both overall architecture and ac...

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Metabolism and Tissue Distribution of Orally Administered Trichloroethylene in Male and Female Rats: Identification of Glutathione- and Cytochrome P-450-Derived Metabolites in Liver, Kidney, Blood, and Urine

Cited by 44 publications

References 45 publications

Trichloroethylene biotransformation and its role in mutagenicity, carcinogenicity and target organ toxicity

Trichloroethylene biotransformation and its role in mutagenicity, carcinogenicity and target organ toxicity

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

Structures of aminoacylase 3 in complex with acetylated substrates

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