Hydroquinone glutathione conjugation

Puckett-Vaughn, D.L., Stenken. J.A.. Scott. D.O., Lunte. S.M. Lunte. C.E. (1993) Enzymatic formation and electrochemical characterization of multiply substituted glutathione conjugates of hydroquinone. Life Sci.. 52. 1239-1247... 

Erve JC, Svensson MA, von Euler-Chelpin H, et al. Characterization of glutathione conjugates of the remoxipride hydroquinone metabolite NCQ-344 formed in vitro and detection following oxidation by human neutrophils. Chem Res Toxicol. 2004 17(4) 564-571. 

Aromatic hydroxylation such as that depicted in figure 4,3 for the simplest aromatic system, benzene, is an extremely important biotransformation. The major products of aromatic hydroxylation are phenols, but catechols and quinols may also be formed, arising by further metabolism. One of the toxic effects of benzene is to cause aplastic anaemia, which is believed to be due to an intermediate metabolite, possibly hydroquinone. As a result of further metabolism of epoxide intermediates (see below), other metabolites such as diols and glutathione conjugates can also... 

Covalent protein adducts of quinones are formed through Mchael-type addihon reachon with protein sulfhydryl groups or glutathione. Metabolic activahon of several toxins (e.g., naphthalene, pentachlorophenol, and benzene) into quinones has been shown to result in protein quinone adducts (Lin et al, 1997 Rappaport et al, 1996 Zheng et al., 1997). Conversion of substituted hydroquinones such as p-aminophenol-hydroquinone and 2-bromo-hydroquinone to their respective glutathione S-conjugates must occur to allow bioactivation into nephrotoxic metabolites (Dekant, 1993). Western blot analysis of proteins from the kidneys of rats treated with 2-bromo-hydroquinone has revealed three distinct protein adducts conjugated to quinone-thioethers (Kleiner et al, 1998). 

Figure 4.65 Oxidation of hydroquinone to quinone and multiple conjugation with glutathione. Biliary excretion of the conjugate and reabsorption allow further metabolism (phase 3) in the gut and kidney to the cysteine conjugate, which is nephrotoxic.

Catechol may be oxidized by peroxidases to the reactive intennediate benzo-1,2-quinone, which readily binds to proteins (Bhat et al., 1988) this process, catalysed by rat or human bone-marrow cells in the presence of H2O2 (0.1 mM), is stimulated by phenol (0.1-10 mM), and decreased by hydroquinone and by glutathione, which conjugates with benzo-l,2-quinone. These phenols (phenol, catechol and hydroquinone) may play a role in benzene toxicity to bone marrow all three are formed as benzene metabolites (Smith et al., 1989) and they interact in several ways as far as their bioactivation by (myelo)peroxidases is concerned (Smith et al., 1989 Subrahmanyam et al., 1990). 

The metabolism of hydroquinone seems very similar in man and rodents sulfate and glucuronide conjugates are the major metabolites. Through the 1,4-benzoquinone metabolite, a reactive intermediate can be formed, in particular in macrophages by peroxidases, that may be trapped by conjugation with glutathione. The reactive intermediate may form DNA adducts, and may also be responsible for kidney toxicity. 

Hydroquinone is metabolized mainly to conjugates, but a small percentage may be converted to 1,4-benzoquinone, conjugated with glutathione or fonn DNA adducts in vitro. 

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