Glutathione-dependent bioactivation of xenobiotics

Abstract

Glutathione conjugation has been identified as an important detoxication reaction. However, in recent years several glutathione-dependent bioactivation reactions have been identified. Current knowledge on the mechanisms and the possible biological importance of these reactions are discussed. 1. Dichloromethane is metabolized by glutathione conjugation to formaldehyde via S-(chloromethyl)glutathione. Both compounds are reactive intermediates and may be responsible for the dichloromethane-induced tumorigenesis in sensitive species. 2. Vicinal dihaloalkanes are transformed by glutathione S-transferase-catalyzed reactions to mutagenic and nephrotoxic S-(2-haloethyl)glutathione S-conjugates. Electrophilic episulphonium ions are the ultimate reactive intermediates formed. 3. Several polychlorinated alkenes are bioactivated in a complex, glutathione-dependent pathway. The first step is hepatic glutathione S-conjugate formation followed by cleavage to the corresponding cysteine S-conjugates, and, after translocation to the kidney, metabolism by renal cysteine conjugate beta-lyase. Beta-Lyase-dependent metabolism of halovinyl cysteine S-conjugates yields electrophilic thioketenes, whose covalent binding to cellular macromolecules is responsible for the observed toxicity of the parent compounds. 4. Finally, hepatic glutathione conjugate formation with hydroquinones and aminophenols yields conjugates that are directed to gamma-glutamyltransferase-rich tissues, such as the kidney, where they undergo alkylation or redox cycling reactions, or both, that cause organ-selective damage.

Biotransformation of the Fungicide Chlorthalonil by Glutathione Conjugation

“…The structures of the formed glutathione 5-conjugates have not been elucidated, but the rapid glutathione depletion indicates that glutathione 5-conjugate formation may be also a pathway for the biotransformation of chlorthalonil in rats in vivo. In general, glutathione 5-conjugate formation is associated with detoxification (Jakoby, 1978;Armstrong, 1987;Jakoby and Ziegler, 1990;Ziegler, 1991); however, several classes of nephrotoxic xenobiotics have been demonstrated to be transformed to toxic glutathione 5-conjugates (Monks etal, 1990;Dekant, 1993;Dekant and Vamvakas, 1993;Lock, 1993). The organ-selective toxicity of these compounds and the derived 5-conjugates is very likely based on the ability of the kidney to process and accumulate glutathione 5-conjugates.…”

Dietary Sulforaphane in Cancer Chemoprevention: The Role of Epigenetic Regulation and HDAC Inhibition

“…Specifically, molecular epidemiological studies involved in elucidating the association between GST-M1 and GST-T1 genotypes with cancer susceptibility have shown that those who carry the homozygous deletion appear to have a small increase in the magnitude of risk (odds ratio of < 2); however, other factors (i.e., cigarette smoking) further enhance the risk (odds ratio of 3-5) (228). This is accounted to their ability to regulate the conjugation of carcinogenic compounds, including benzo(a)pyrene and styrene-7,8-oxide by GST-M1, and ethylene oxide and methyl bromide by GST-T1, to excretable hydrophilic metabolites (10,59,97,316). Through the inability to express functional GST enzymes, individuals possessing the homozygous null genotype have a limited capacity to efficiently detoxify potentially carcinogenic exposures.…”

Thyroid hormone and estradiol have overlapping effects on kidney glutathioneS-transferase-α gene expression

“…They are involved in the kidney activation of cytotoxic compounds (46) because the circulating glutathione S conjugates are bioactivated in the kidney by ␥-glutamyltransferase and ␤-lyase, which create these nephrotoxins (14). It has been known for some time that, in the liver, GST gene expression and activity are regulated by several exogenous factors, such as dexamethasone and phenobarbital (45), and by a variety of antioxidant compounds (18,28,47).…”