Molecular mechanism of metal-independent decomposition of lipid hydroperoxide 13-HPODE by halogenated quinoid carcinogens

Abstract

Halogenated quinones are a class of carcinogenic intermediates and newly identified chlorination disinfection by-products in drinking water. 13-Hydroperoxy-9,11-octadecadienoic acid (13-HPODE) is the most extensively studied endogenous lipid hydroperoxide. Although it is well known that the decomposition of 13-HPODE can be catalyzed by transition metal ions, it is not clear whether halogenated quinones could enhance its decomposition independent of metal ions and, if so, what the unique characteristics and similarities are. Here we show that 2,5-dichloro-1,4-benzoquinone (DCBQ) could markedly enhance the decomposition of 13-HPODE and formation of reactive lipid alkyl radicals such as pentyl and 7-carboxyheptyl radicals, and the genotoxic 4-hydroxy-2-nonenal (HNE), through the complementary application of ESR spin trapping, HPLC-MS, and GC-MS methods. Interestingly, two chloroquinone-lipid alkoxyl conjugates were also detected and identified from the reaction between DCBQ and 13-HPODE. Analogous results were observed with other halogenated quinones. This represents the first report that halogenated quinoid carcinogens can enhance the decomposition of the endogenous lipid hydroperoxide 13-HPODE and formation of reactive lipid alkyl radicals and genotoxic HNE via a novel metal-independent nucleophilic substitution coupled with homolytic decomposition mechanism, which may partly explain their potential genotoxicity and carcinogenicity.

Keywords: 13-HPODE; 13-Hydroperoxy-9,11-octadecadienoic acid; 13-hydroperoxy-9,11-octadecadienoic acid; 2,5-dichloro-1,4-benzoquinone; 2-chloro-5-(L-13-OO)-1,4-benzoquinone; 2-chloro-5-hydroxy-1,4-benzoquinone; 2-chloro-5-t-butylperoxyl-1,4-benzoquinone; 2-hydroxy-3-(L-13-oxy)-5-chloro-1,4-benzoquinone; 2-hydroxy-3-(OL-9-oxy)-5-chloro-1,4-benzoquinone; 2-hydroxy-3-t-butoxy-5-chloro-1,4-benzoquinone; 4-Hydroxy-2-nonenal; 4-hydroxy-2-nonenal; 5,5-dimethyl-1-pyrroline N-oxide; CBQ(OH)–13-O–L; CBQ(OH)–9-O–LO; CBQ(OH)–O–t-Bu; CBQ–13-OOL; CBQ–OH; CBQ–OO–t-Bu; DCBQ; DMPO; ESR; ESR spin trapping; FTICR–MS; Fourier transform ion cyclotron resonance–mass spectrometry; Free radicals; GC–MS; HNE; HPLC–MS; Halogenated quinones; LPO; Lipid alkyl radicals; POBN; electron spin resonance; gas chromatography–mass spectrometry; high-performance liquid chromatography–mass spectrometry; lipid peroxidation; t-BuOOH; t-butylhydroperoxide; α-(4-pyridyl-1-oxide)-N-tert-butyl nitrone.