Formation and Fate of Nephrotoxic and Cytotoxic Glutathione S-Conjugates: Cysteine Conjugate β-Lyase Pathway

Dekant, W.; Vamvakas, Spyridon; Andersl, M.W.

doi:10.1016/s1054-3589(08)61031-5

Cited by 95 publications

(91 citation statements)

References 206 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Induction of GGT activity and increased intracellular glutathione concentrations have been correlated with increased resistance of tumors to chemotherapeutic drugs (Godwin et al, 1992;Lau et al, 1991;Lewis et al, 1988). In contrast, cisplatin and a series of halogenated hydrocarbons require GGT activity in the kidney to be converted to nephrotoxins (Dekant et al, 1995;Hanigan et al, 1994b). We are analyzing the distribution of GGT in human tumors with the GGT129 antibody and examining the relationship between GGT expression and the response of tumors to chemotherapy.…”

Section: Discussionmentioning

confidence: 99%

Immunohistochemical detection of gamma-glutamyl transpeptidase in normal human tissue.

Hanigan¹,

Frierson²

1996

J Histochem Cytochem.

178

166

View full text Add to dashboard Cite

We developed a new, highly specific antibody that localizes y-glutamyl transpeptidase (GGT) in formalin-fd sections of human tissue. The specificity of the antibody, GGT129, is demonstrated by immunostained Westem blots of whole cell homogenate from five Merent tissues. The utility of the antibody is shown by a comprehensive study of GGT expression in normal human tissue. This study reveals GGT expression for the fmt time in a number of tissues, induding glands in the endocervix, endometrium, and adrenals. Strong immunoreactivity was observed on the surface of renal proximal tubule cells, hepatic bile canaliculi, and capillary endothelial cells within the nervous system. Secretory

show abstract

Section: Discussionmentioning

confidence: 99%

Immunohistochemical detection of gamma-glutamyl transpeptidase in normal human tissue.

Hanigan¹,

Frierson²

1996

J Histochem Cytochem.

178

166

View full text Add to dashboard Cite

show abstract

“…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.…”

mentioning

confidence: 99%

“…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.

View full text Add to dashboard Cite

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...

show abstract

“…The additional oxidation of M20 at the 5-methyl group results in the formation of M21, which undergoes the subsequent glucuronidation to form the O-glucuronide conjugate M21-G. The enzymatic processing for degradation of gluthathione S-conjugate to yield thio-conjugate is well understood (Dekant et al, 1994). The evidence to support this mechanism derived from the detection of the cysteine and mercapturate S-conjugates of valdecoxib in rabbit urine (J. Zhang, unpublished works).…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics and Metabolism of a COX-2 Inhibitor, Valdecoxib, in Mice

Zhang¹,

Yuan²,

Wang³

et al. 2003

Drug Metab Dispos

View full text Add to dashboard Cite

This article is available online at http://dmd.aspetjournals.org ABSTRACT:The pharmacokinetics and metabolism of valdecoxib, a potent cyclooxygenase-2 selective inhibitor, were investigated in mice. Valdecoxib, 4-(5-methyl-3-phenylisoxazol-4-yl)benzenesulfonamide, is a new anti-inflammatory drug that is highly selective for inhibition of the inducible form of cyclooxygenase (COX-2 1 ) in in vitro enzymatic assays (Talley et al., 2000). This drug (BEXTRA, Pharmacia Corporation) was approved recently by the U.S. Food and Drug Administration for the treatment of rheumatoid arthritis, osteoarthritis, and primary dysmenrrhea (Camu et al., 2002;Fricke et al., 2002). Valdecoxib is the second generation COX-2 inhibitor developed by Pharmacia after celecoxib, the first approved COX-2 inhibitor. These new types of anti-inflammatory drugs are developed based on the hypothesis that selective inhibition of COX-2 should decrease inflammation without the adverse gastrointestinal effects associated with inhibition of the constitutive cyclooxygenase (COX-1) (Donnelly and Hawkey, 1997;Pennisi, 1998;Vane et al., 1998). Clinical studies have demonstrated that COX-2 inhibitors lead to a significant reduction in joint pain, joint tenderness/pain, and joint swelling with a statistically-significantly lower incidence of gastric ulceration Simon et al., 1998). Additionally, recent studies demonstrated that COX-2 inhibitors appear to provide some relief for preventing colon cancer and Alzheimer's disease (Elder and Paraskeva, 1998;Hecker, 1998;Pennisi, 1998;Ziegler, 1998).We have recently reported the absorption, distribution, metabolism, and excretion of valdecoxib in humans (Yuan et al., 2002). The primary oxidative metabolic pathways of valdecoxib in humans involved in hydroxylation at either the methyl group to form a hydroxymethyl metabolite or N-hydroxylation at the sulfonamide moiety to form an N-hydroxy metabolite. Further oxidation of the hydroxymethyl metabolite led to the formation of several other phase I metabolites. Oxidative breakdown of the N-hydroxy sulfonamide functional group in the N-hydroxy metabolite led to the formation of corresponding sulfinic acid and sulfonic acid metabolites. The Oglucuronidation of the hydroxymethyl metabolite and N-glucuronidation of valdecoxib were the major metabolites in human urine. The objectives of this study were to determine the total radioactivity recovery in male and female mice following a single oral administration of [ 14 C]valdecoxib at 5 mg/kg, to obtain metabolic profiles in selected mouse plasma RBC, urine, and fecal samples, to identify the major metabolites of valdecoxib, to estimate plasma and RBC pharmacokinetic parameters for total radioactivity, and to examine gender difference in pharmacokinetics of valdecoxib and major metabolites. Materials and Methods Chemicals. Valdecoxib and [14 C]valdecoxib (uniformly labeled at the six carbons of 3-phenyl ring) were synthesized at Pharmacia Corporation (Skokie, IL). The specific activity of [ 14 C]valdecoxib was approximately 5...

show abstract

Formation and Fate of Nephrotoxic and Cytotoxic Glutathione S-Conjugates: Cysteine Conjugate β-Lyase Pathway

Cited by 95 publications

References 206 publications

Immunohistochemical detection of gamma-glutamyl transpeptidase in normal human tissue.

Immunohistochemical detection of gamma-glutamyl transpeptidase in normal human tissue.

Structures of aminoacylase 3 in complex with acetylated substrates

Pharmacokinetics and Metabolism of a COX-2 Inhibitor, Valdecoxib, in Mice

Contact Info

Product

Resources

About