Role of Cu/Zn-superoxide dismutase in xenobiotic activation. I. Chemical reactions involved in the Cu/Zn-superoxide dismutase-accelerated oxidation of the benzene metabolite 1,4-hydroquinone

Yunbo Li, Periannan Kuppusamy, Jay L. Zweier, Michael A. Trush

Research output: Contribution to journalArticle

Abstract

Cu/Zn-superoxide dismutase (Cu/Zn-SOD) has been shown to modulate the autoxidation of a variety of phenolic compounds, including 1,4-hydroquinone (HQ), a benzene-derived metabolite. The acceleration of autoxidation of HQ by Cu/Zn-SOD results in the production of 1,4-benzoquinone (BQ). It has been proposed that the chemical mechanism involved in the Cu/Zn-SOD-catalyzed autoxidation of HQ may be occur through either its conventional activity as a superoxide:superoxide oxidoreductase or as a semiquinone:superoxide oxidoreductase. However, which of the above two mechanisms is responsible for the Cu/Zn-SOD-accelerated oxidation of HQ has not been resolved experimentally. In this study, with ESR spectroscopy we investigated further the chemical reactions involved in the SOD-accelerated oxidation of HQ. In phosphate-buffered saline (PBS), HQ underwent a slow autoxidation to BQ, which was accelerated by Cu/Zn-SOD, Mn-SOD, or Fe-SOD with a similar efficiency. In contrast, among free metals, only Cu(II) strongly mediated the oxidation of HQ to BQ. Mn(II) exhibited a slight capacity to oxidize HQ, whereas neither Fe(II) nor Fe(III) was capable of modulating the autoxidation of HQ. The presence of either form of SOD also dramatically enhanced the formation of semiquinone anion radicals (SQ·) from HQ. The SOD-accelerated oxidation of HQ was also accompanied by the generation of H2O2. In PBS containing bovine serum albumin (BSA) (PBS/BSA), HQ did not undergo autoxidation to SQ·, and as such the presence of SOD was unable to induce the formation of either SQ· or BQ or the consumption of O2. The addition of 10 μM BQ to HQ (100 or 1000 μM) in PBS/BSA resulted in the formation of SQ· and initiated a slow rate of oxidation of HQ to BQ. In this case, the presence of Cu/Zn-SOD strongly accelerated the oxidation of HQ to SQ-· and BQ and the utilization of O2. Furthermore, the enhancement by Cu/Zn-SOD of the generation of SQ-· or BQ from HQ in PBS/BSA was extensively inhibited under anaerobic conditions. The enhancement of SQ· generation from HQ by all three forms of SOD does not support the possibility that Cu/Zn-SOD can oxidize SQ-· to BQ. Taken together, this study demonstrates that unlike free copper, Cu/Zn-SOD does not directly interact with HQ to cause its oxidation to BQ. Rather, the autoxidation of HQ to SQ-· is a prerequisite for the enhancing capacity of Cu/Zn-SOD, and the dismutation of superoxide anion radicals generated from the SQ· in the presence of O2 appears to be the underlying mechanism responsible for the enhancement by Cu/Zn-SOD of the oxidation of HQ.

Original languageEnglish (US)
Pages (from-to)404-411
Number of pages8
JournalMolecular Pharmacology
Volume49
Issue number3
StatePublished - Mar 1 1996

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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