title: Potential roles of myeloperoxidase and hypochlorous acid in metabolism and toxicity of alkene hydrocarbons and drug molecules containing olefinic moieties.
abstract: Adverse drug reactions (ADRs) pose a significant health problem and are generally attributed to reactive metabolites. Olefinic moieties in drugs can undergo cytochrome P450-mediated bioactivation to produce reactive metabolites but myeloperoxidase (MPO)-mediated bioactivation of these moieties has not been reported. Thus, small molecules of alkene hydrocarbons are used as model compounds to characterize the MPO-mediated metabolism. Areas covered: The authors focus on MPO-mediated metabolism of alkene hydrocarbons to form chlorohydrins and the potential role of chlorohydrins in alkene toxicity and carcinogenicity. A case study is presented, in which a carcinogenic alkene, 1,3-butadiene, is demonstrated to form 1-chloro-2-hydroxy-3-butene (CHB) through the MPO-mediated pathway. Further bioactivation of CHB yields a cross-linking metabolite, 1-chloro-3-buten-2-one (CBO), which is highly reactive toward glutathione, proteins, nucleosides, and DNA. Toxicity and mutagenicity of CHB and CBO are also presented. Expert opinion: Alkene hydrocarbons readily undergo MPO-mediated bioactivation to form chlorohydrins, which can further be biotransformed into proteins/DNA-modifying reactive metabolites. Therefore, chlorohydrin formation may play an important role in alkene toxicity and carcinogenicity. Olefinic moieties in drugs are expected to undergo similar bioactivation, which may contribute to ADRs. Studies to investigate the roles of MPO and chlorohydrin formation in ADRs are thus warranted.
authors.affiliation: a Institute of Environmental Pollution and Health, School of Environmental and Chemical Engineering , Shanghai University , Shanghai , China.
authors.forename: Xin-Yu
authors.initials: XY
authors.lastname: Zhang
authors.affiliation: b Department of Comparative Biosciences and the Molecular and Environmental Toxicology Center , University of Wisconsin-Madison , Madison , WI , USA.
authors.forename: Adnan A
authors.initials: AA
authors.lastname: Elfarra
mesh_terms: D000475:Alkenes / Q000009:adverse effects / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D002070:Butadienes / Q000378:metabolism / Q000633:toxicity; D002273:Carcinogens / Q000378:metabolism / Q000633:toxicity; D002728:Chlorohydrins / Q000009:adverse effects / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D006838:Hydrocarbons / Q000009:adverse effects / Q000737:chemistry / Q000378:metabolism; D006997:Hypochlorous Acid / Q000378:metabolism*; D009195:Peroxidase / Q000378:metabolism*
chemical_list: D000475:Alkenes; D002070:Butadienes; D002273:Carcinogens; D002728:Chlorohydrins; D006838:Hydrocarbons; D006997:Hypochlorous Acid; D009195:Peroxidase; C031763:1,3-butadiene
keywords: Adverse drug reactions; bioactivation; chlorohydrin formation; hypochlorous acid; myeloperoxidase