Dose-dependent induction or depression of cysteine conjugate β-lyase in rat kidney by N-acetyl-S-(1,2,3,4,4-pentachloro-1,3-butadienyl)-L-cysteine

doi:10.1016/0300-483X(93)90144-H

Toxicology

Volume 77, Issues 1–2, 29 January 1993, Pages 133-144

https://doi.org/10.1016/0300-483X(93)90144-H Get rights and content

Abstract

The influence of $N- acetyl -S-(1,2,3,4,4- pentachloro -1,3- butadienyl - L -cysteine$ (NAc-PCBD) on cysteine conjugate β-lyase in femlae rat kidney has been examined. After a single, non-nephrotoxic dose of NAc-PCBD (3 mg/kg), cytosolic β-lyase enzyme activity was increased 1.5 to 3-fold commensurate with corresponding increase in enzyme protein levels as assessed by both Western blot and ELIS analyses. Using a cDNA probe for β-lyase, this induction was found to be accompanied by an increase in the cognate mRNA. In contrast, a higher, nephotoxic dose of NAc-PCBD (10 mg/kg) decreased all the above parameters. These effects appeared to be specific to the cytosolic form of the enzyme as no changes in kidney mitochondrial β-lyase activity or enzyme protein levels were observed. Repeated dosing with the lower dose level (3 mg/kg) resulted in either no change, or in some instances, a reduction in the above parameters, suggesting an accumulation of the xenobiotic and a masking of the induction phenomenon. The molecular mechanisms underlying these observation are discussed in terms of the nephorotoxicity of halogenated xenobiotics.

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Many potentially toxic electrophilic xenobiotics and some endogenous compounds are detoxified by conversion to the corresponding glutathione S-conjugate, which is metabolized to the N-acetylcysteine S-conjugate (mercapturate) and excreted. Some mercapturate pathway components, however, are toxic. Bioactivation (toxification) may occur when the glutathione S-conjugate (or mercapturate) is converted to a cysteine S-conjugate that undergoes a β-lyase reaction. If the sulfhydryl-containing fragment produced in this reaction is reactive, toxicity may ensue. Some drugs and halogenated workplace/environmental contaminants are bioactivated by this mechanism. On the other hand, cysteine S-conjugate β-lyases occur in nature as a means of generating some biologically useful sulfhydryl-containing compounds.
Enzymes Involved in Processing Glutathione Conjugates
2010, Comprehensive Toxicology, Second Edition
Many potentially toxic electrophiles react with glutathione to form glutathione S-conjugates in reactions catalyzed or enhanced by glutathione S-transferases. The glutathione S-conjugate is sequentially converted to the cysteinylglycine-, cysteine- and N-acetyl-cysteine S-conjugate (mercapturate). The mercapturate is generally more polar and water soluble than the parent electrophile and is readily excreted. Excretion of the mercapturate represents a detoxication mechanism. Some endogenous compounds, such as leukotrienes, prostaglandin (PG) A2, 15-deoxy-Δ^12,14-PGJ₂, and hydroxynonenal can also be metabolized to mercapturates and excreted. On occasion, however, formation of glutathione S- and cysteine S-conjugates are bioactivation events as the metabolites are mutagenic and/or cytotoxic. When the cysteine S-conjugate contains a strong electron-withdrawing group attached at the sulfur, it may be converted by cysteine S-conjugate β-lyases to pyruvate, ammonium and the original electrophile modified to contain an –SH group. If this modified electrophile is highly reactive then the enzymes of the mercapturate pathway together with the cysteine S-conjugate β-lyases constitute a bioactivation pathway. Some endogenous halogenated environmental contaminants and drugs are bioactivated by this mechanism. Recent studies suggest that coupling of enzymes of the mercapturate pathway to cysteine S-conjugate β-lyases may be more common in nature and more widespread in the metabolism of electrophilic xenobiotics than previously realized.
Interactive toxicity of inorganic mercury and trichloroethylene in rat and human proximal tubules: Effects on apoptosis, necrosis, and glutathione status
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Simultaneous or prior exposure to one chemical may alter the concurrent or subsequent response to another chemical, often in unexpected ways. This is particularly true when the two chemicals share common mechanisms of action. The present study uses the paradigm of prior exposure to study the interactive toxicity between inorganic mercury (Hg²⁺) and trichloroethylene (TRI) or its metabolite S-(1,2-dichlorovinyl)-l-cysteine (DCVC) in rat and human proximal tubule. Pretreatment of rats with a subtoxic dose of Hg²⁺ increased expression of glutathione S-transferase-α1 (GSTα1) but decreased expression of GSTα2, increased activities of several GSH-dependent enzymes, and increased GSH conjugation of TRI. Primary cultures of rat proximal tubular (rPT) cells exhibited both necrosis and apoptosis after incubation with Hg²⁺. Pretreatment of human proximal tubular (hPT) cells with Hg²⁺ caused little or no changes in GST expression or activities of GSH-dependent enzymes, decreased apoptosis induced by TRI or DCVC, but increased necrosis induced by DCVC. In contrast, pretreatment of hPT cells with TRI or DCVC protected from Hg²⁺ by decreasing necrosis and increasing apoptosis. Thus, whereas pretreatment of hPT cells with Hg²⁺ exacerbated cellular injury due to TRI or DCVC by shifting the response from apoptosis to necrosis, pretreatment of hPT cells with either TRI or DCVC protected from Hg²⁺-induced cytotoxicity by shifting the response from necrosis to apoptosis. These results demonstrate that by altering processes related to GSH status, susceptibilities of rPT and hPT cells to acute injury from Hg²⁺, TRI, or DCVC are markedly altered by prior exposures.
Isolation from rat kidney of a cytosolic high molecular weight cysteine-S-conjugate β-lyase with activity toward leukotriene E<inf>4</inf>
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A cytosolic high M_r cysteine-S-conjugate β-lyase (apparent M_r of ∼330,000) has been partially purified from rat kidneys. The high M_r lyase is also present in the mitochondria. The purified enzyme contains at least two proteins with apparent M_r values of ∼50,000 and ∼70,000. Activity is stimulated by dithiothreitol, α-keto acids, and pyridoxal 5′-phosphate; aminooxyacetate is an inhibitor. The enzyme catalyzes a competing (half) transamination reaction between pyridoxal 5′-phosphate cofactor and cysteine-S-conjugate substrate; added α-keto acids promote conversion of active site pyridoxamine 5′-phosphate to pyridoxal 5′-phosphate. The enzyme also catalyzes a full (but weak) transamination between L-phenylalanine and α-keto-γ-methiolbutyrate. The purified enzyme is not recognized by polyclonal rabbit antibodies to cytosolic rat kidney glutamine transaminase K (another cysteine-S-conjugate β-lyase of rat kidney) and has no obvious similarities to other pyridoxal 5′-phosphate-containing enzymes. In addition to catalyzing elimination reactions with S-(1,2-dichlorovinyl)-L-cysteine and S-(1,1,2,2-tetrafluoroethyl)-L-cysteine, the enzyme reacts with leukotriene E₄ and 5′-S-cysteinyldopamine. Finally, the cytosolic and mitochondrial enzymes are activated by α-ketoglutarate. Thus, the possibility must be considered that, in kidneys of animals exposed to various cysteine conjugates, the high M_r lyase contributes to the generation of pyruvate, ammonia, and reactive fragments in vivo. Many cysteine conjugates are nephrotoxic, and the high M_r lyase(s) may be involved.
Enzymology of Cysteine S-Conjugote β-Lyases
1994, Advances in Pharmacology
This chapter addresses recent findings concerning the identity of the cysteine S-conjugate β-lyases in mammals, the reactions catalyzed by these enzymes, and the pharmacological aspects of the cysteine S-conjugate β-lyases are addressed. It also discusses β-elimination reactions with cysteine S-conjugates in detail. Relatively little attention has been given to the role of cysteine S-conjugates in human health. Prolonged exposure to low levels of pollutants that can be activated through a glutathione conjugate may predispose certain individuals to risk of kidney disease and others perhaps to inexorable loss of brain function. From this epidemiological point of view, the cysteine S-conjugate β-lyases deserve more attention. However, these enzymes are also interesting in their own right. Cysteine S-conjugate β-lyases thus far shown to occur in mammals belong to three classes: (1) those present in enteric bacteria, (2) a liver form (kynureninase), and (3) a kidney form (glutamine transaminase K). In addition, because of its unique substrate specificity, the enzyme may be the target of prodrugs designed to deliver anticancer drugs to the kidney. Indeed, some progress has already been made in this area.
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Dose-dependent induction or depression of cysteine conjugate β-lyase in rat kidney by N-acetyl-S-(1,2,3,4,4-pentachloro-1,3-butadienyl)-L-cysteine

Abstract

Chem.-Biol. Interact.

Chem. Biol. Interact.

Toxicol. Appl. Pharmacol.

Food Chem. Toxicol.

Biochem. Biophys. Res. Commun.

Toxicol. Appl. Pharmacol.

J. Biol. Chem.

Methods Enzymol.

Anal. Biochem.