Potential roles of myeloperoxidase and hypochlorous acid in metabolism and toxicity of alkene hydrocarbons and drug molecules containing olefinic moieties

ABSTRACT

Introduction: 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.

KEYWORDS:

• Adverse drug reactions
• myeloperoxidase
• hypochlorous acid
• chlorohydrin formation
• bioactivation

Article highlights

• Adverse drug reactions (ADRs) form a major challenge in drug discovery and development, and are generally attributed to the formation of reactive metabolites. Alkenes or olefins are a class of structural motifs that are present in many pharmaceutical drugs and have potential to be bioactivated to reactive metabolites. However, limited attention has been paid to olefinic moieties in drugs and their metabolism. Olefinic moieties in drugs can be bioactivated to epoxides by cytochrome P450s but their bioactivation by peroxidases, especially myeloperoxidase (MPO), has not been reported. Thus, small molecules of alkene hydrocarbons are used as model compounds to elucidate the potential significance of MPO-mediated bioactivation of olefinic moieties in drugs.

• Toxicity and carcinogenicity of small molecules of alkene hydrocarbons are generally attributed to reactive epoxide metabolites, which are formed primarily via the cytochrome P450-mediated pathway. This pathway is active in the liver, lung, and kidney because P450s are abundant in these organs. However, it has been difficult to explain their carcinogenicity in exposed humans, because the target organ for carcinogenicity of small molecules of alkene hydrocarbons, e.g., 1,3-butadiene and styrene, is the lymphohematopoietic system.

• Small molecules of alkene hydrocarbons can also be bioactivated into chlorohydrins via an alternative metabolic pathway, which is mediated by MPO, an enzyme abundant in bone marrow cells and neutrophils. In this pathway, chloride ion is oxidized by hydrogen peroxide under catalysis of MPO to produce hypochlorous acid (HOCl) and addition of HOCl to alkenes occurs readily at physiological conditions to generate chlorohydrins. Chlorohydrins have diverse chemical structures depending upon the alkenes and can further be bioactivated by alcohol dehydrogenase and/or other cellular enzymes to yield reactive metabolites that readily react with glutathione, proteins, and DNA. Chlorohydrins can also cause cytotoxicity, genotoxicity, mutagenicity, and carcinogenicity.

• MPO-generated chlorohydrins may play an important role in myelotoxicity and carcinogenicity of small molecules of alkene hydrocarbons, in addition to the epoxides generated in situ or translocated via the circulation from the liver and other tissues to the bone marrow. The MPO-mediated pathway may also provide opportunities for elucidation of alkene toxicity because neutrophils play a central role in the innate and adaptive immune systems, and MPO and chronic inflammation is involved in a variety of modern human diseases, e.g., type 2 diabetes, atherosclerosis, autoimmunity, allergy, and neurodegenerative diseases.

• Olefinic moieties in drugs are expected to undergo similar MPO-mediated bioactivation to form chlorohydrins, which may contribute to ADRs.

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Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

The authors are supported by grants from theNational Nature Science Foundation of China (Nos. 21077070 and 21377080), the Shanghai Municipal Education Commission (No. 11ZZ90), The Shanghai Leading Academic Discipline Project (No. S30109), and the National Institutes of Health of the USA (R01 DK044295 and R01 ES06841).