Oxidative cyclization, 1,4-benzothiazine formation and dimerization of 2-bromo-3-(glutathion-S-yl)hydroquinone

Terrence Monks, Robert J. Highet, Serrine Lau

Research output: Contribution to journalArticle

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Abstract

Several lines of evidence suggest that the renal-specific toxicity of quinol-linked GSH conjugates is probably a result of their metabolism by γ-glutamyl transpeptidase and selective accumulation by proximal tubular cells. Transport of the resultant quinol-cysteine and/or cystein-S-ylglycine conjugate followed by oxidation to the quinone may be important steps in the mechanism of toxicity of these compounds. Factors modulating the intracellular and/or intralumenal concentration of the cystein-S-yl and cystein-S-ylglycine conjugate will, therefore, be important determinants of toxicity. We have now studied the γ-glutamyl transpeptidase-mediated metabolism of 2-bromo-3-(glutathion-S-yl)hydroquinone. The product of this reaction, 2-bromo-3-(cystein-S-ylglycyl)hydroquinone, undergoes an intramolecular cyclization to yield a 1,4-benzothiazine derivative that retains the glycine residue. A similar cyclization reaction occurs with 2-bromo-3-(cystein-S-yl)hydroquinone, which is unstable in aqueous solutions and undergoes a pH-dependent rearrangement that requires initial oxidation to the quinone. UV spectroscopy revealed that, at neutral pH, further reaction results in the formation of a chromophore, consistent with 1,4-benzothiazine formation. This product arises via cyclization of the cysteine residue via an intramolecular 1,4 Michael addition. Further reaction results in the precipitation of a pigment that exhibits properties of a pH indicator. The pigment undergoes a marked pH-dependent bathochromic shift (∼100 nm); it is red in alkali (λmax, 480 nm) and violet in acid (λmax, 578 nm). These properties are similar to those of the trichochrome polymers that are formed during melanin biosynthesis from S-(3,4-dihydroxyphenyl-alanine)-L-cysteine. Because the intramolecular cyclization reactions remove the reactive quinone moiety from the molecules, they may be regarded as detoxication reactions. 1,4-Benzothiazine formation represents a novel pathway that diverges from the usual route of mercapturic acid synthesis and may represent previously unrecognized and important products of quinone metabolism in vivo.

Original languageEnglish (US)
Pages (from-to)121-127
Number of pages7
JournalMolecular Pharmacology
Volume38
Issue number1
StatePublished - Jul 1990
Externally publishedYes

Fingerprint

Dimerization
Cyclization
Hydroquinones
Cysteine
gamma-Glutamyltransferase
Melanins
Acetylcysteine
Alkalies
Alanine
Glycine
Spectrum Analysis
Polymers
Kidney
Acids
1,4-benzothiazine
2-bromo-3-(glutathion-S-yl)hydroquinone
benzoquinone
hydroquinone

ASJC Scopus subject areas

  • Pharmacology

Cite this

Oxidative cyclization, 1,4-benzothiazine formation and dimerization of 2-bromo-3-(glutathion-S-yl)hydroquinone. / Monks, Terrence; Highet, Robert J.; Lau, Serrine.

In: Molecular Pharmacology, Vol. 38, No. 1, 07.1990, p. 121-127.

Research output: Contribution to journalArticle

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abstract = "Several lines of evidence suggest that the renal-specific toxicity of quinol-linked GSH conjugates is probably a result of their metabolism by γ-glutamyl transpeptidase and selective accumulation by proximal tubular cells. Transport of the resultant quinol-cysteine and/or cystein-S-ylglycine conjugate followed by oxidation to the quinone may be important steps in the mechanism of toxicity of these compounds. Factors modulating the intracellular and/or intralumenal concentration of the cystein-S-yl and cystein-S-ylglycine conjugate will, therefore, be important determinants of toxicity. We have now studied the γ-glutamyl transpeptidase-mediated metabolism of 2-bromo-3-(glutathion-S-yl)hydroquinone. The product of this reaction, 2-bromo-3-(cystein-S-ylglycyl)hydroquinone, undergoes an intramolecular cyclization to yield a 1,4-benzothiazine derivative that retains the glycine residue. A similar cyclization reaction occurs with 2-bromo-3-(cystein-S-yl)hydroquinone, which is unstable in aqueous solutions and undergoes a pH-dependent rearrangement that requires initial oxidation to the quinone. UV spectroscopy revealed that, at neutral pH, further reaction results in the formation of a chromophore, consistent with 1,4-benzothiazine formation. This product arises via cyclization of the cysteine residue via an intramolecular 1,4 Michael addition. Further reaction results in the precipitation of a pigment that exhibits properties of a pH indicator. The pigment undergoes a marked pH-dependent bathochromic shift (∼100 nm); it is red in alkali (λmax, 480 nm) and violet in acid (λmax, 578 nm). These properties are similar to those of the trichochrome polymers that are formed during melanin biosynthesis from S-(3,4-dihydroxyphenyl-alanine)-L-cysteine. Because the intramolecular cyclization reactions remove the reactive quinone moiety from the molecules, they may be regarded as detoxication reactions. 1,4-Benzothiazine formation represents a novel pathway that diverges from the usual route of mercapturic acid synthesis and may represent previously unrecognized and important products of quinone metabolism in vivo.",
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