Association of microsomal epoxide hydrolase gene (fast genotype) with lung functions impairment in wood workers

Objectives Exposure to wood dust may lead to impairment of the lung functions. Microsomal epoxide hydrolase enzyme (EPHX1) was shown to take part in protection against oxidative stress. An alteration in enzyme activity might be associated with its gene polymorphisms. In vitro polymorphisms in exons 3 (His113Tyr) and 4 (Arg139His) lead to reduced activity (slow allele) and increased activity (fast allele). Macrophage inflammatory protein 2 (MIP-2) is produced in rat lung epithelial cells after exposure to fine particles. We aimed to investigate the associations between mEPHX1 polymorphisms (in exon 3 and 4) and lung function in furniture workers and assessment of MIP-2 effect. Methods Our study was performed on 70 wood dust exposed male workers and 70 matched normal controls subjects. Ventilatory function tests were measured by spirometer, MIP-2 was performed by ELISA methods and EPHX gene was done by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methods for each participant. Results Significant reduction in forced vital capacity (FVC%) and forced expiratory volume in the first second (FEV1) levels in Tyr–Tyr and Tyr–Hist genotypes of EPHX (exon 3) was observed. Reduced peak expiratory flow (PEF) levels and significant rise in MIP-2 levels were detected in Tyr–Tyr genotype. While high significant reduction in FVC% and FEV1 levels were shown in different genotypes in exon 4. Significant rise was observed in MIP-2 levels in Hist–Hist genotype of exon 4. An increase in duration of exposure showed positive correlation with fall in ventilatory functions. Conclusions It was concluded that in Hist139Arg of EPHX gene, fast genotype (Arg–Arg) was associated with impaired ventilatory functions.

Ibuprofen alters epoxide hydrolase activity and epoxy-oxylipin metabolites associated with different metabolic pathways in murine livers

Over the last decade oxylipins have become more recognized for their involvement in several diseases. Non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen are known to inhibit cyclooxygenase (COX) enzymes, but how NSAIDs affect oxylipins, in addition to COX products, in animal tissues is not well understood. Oxylipins in livers from male and female mice treated with 100 mg/kg/day of ibuprofen for 7 days were investigated. The results showed that ibuprofen treated male livers contained 7 times more altered oxylipins than ibuprofen treated female livers. In male and female livers some prostaglandins were altered, while diols, hydroxy fatty acids and epoxides were significantly altered in male livers. Some soluble epoxide hydrolase (sEH) products, such as 9,10-DiHODE were found to be decreased, while sEH substrates (such as 9(10)-EpODE and 5(6)-EpETrE) were found to be increased in male livers treated with ibuprofen, but not in ibuprofen treated female livers. The enzymatic activities of sEH and microsomal epoxide hydrolase (mEH) were elevated by ibuprofen in both males and females. Analyzing the influence of sex on the effect of ibuprofen on oxylipins and COX products showed that approximately 27% of oxylipins detected were influenced by sex. The results reveal that ibuprofen disturbs not only the COX pathway, but also the CYP450 and lipoxygenase pathways in male mice, suggesting that ibuprofen is likely to generate sex related differences in biologically active oxylipins. Increased sEH activity after ibuprofen treatment is likely to be one of the mechanisms by which the liver reduces the higher levels of EpODEs and EpETrEs.

Ibuprofen alters epoxide hydrolase activity and epoxy-oxylipin metabolites associated with different metabolic pathways in murine livers

Over the last decade oxylipins have become more recognized for their involvement in several diseases. Non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen are known to inhibit cyclooxygenase (COX) enzymes, but how NSAIDs affect oxylipins, in addition to COX products, in animal tissues is not well understood. Investigation of oxylipins in livers from male and female mice treated with 100mg/kg/day of ibuprofen for 7 days showed that oxylipins and COX products that were altered by ibuprofen in male livers were 7 times more than in female livers. In male and female livers some prostaglandins were altered, while diols, hydroxy fatty acids and epoxides were only significantly altered in male livers. Some soluble epoxide hydrolase (sEH) products, such as 9,10-DiHODE were found to be decreased, while sEH substrates (such as 9(10)-EpODE) were found to be increased in male livers treated with ibuprofen, but not in female livers. The enzymatic activities of sEH and microsomal epoxide hydrolase (mEH) were elevated by ibuprofen in both males and females. Analyzing the influence of sex on the effect of ibuprofen on oxylipins and COX products showed that approximately 27% of oxylipins detected were influenced by sex. The results reveal that ibuprofen disturbs not only the COX pathway, but also the CYP450 and lipoxygenase pathways in male mice, suggesting that ibuprofen is likely to generate sex related differences in biologically active oxylipins. Increased sEH activity is likely to be one of the mechanisms by which ibuprofen alters the CYP450 pathway.