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

Abstract

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.

Factors affecting variability in free oxylipins in mammalian tissues

“…Sex differences in oxylipins in the context of cardiovascular disease has been recently reviewed, highlighting higher levels of prostaglandin E 2 , thromboxane A 2 and epoxy-eicosatrienoic acids and lower levels of prostaglandin I 2 and 20-HETE in females in various rat and mouse tissues [78 ▪ ]. Several other recent studies in rats [19] and mice [74 ▪ ,79] also reveal tissue sex differences, confirming several previous studies [80,81], highlighting that disaggregating data by sex is necessary to reduce variability of oxylipin data.…”

“…Further complicating this, off-target effects may also be prevalent. In mice treated with ibuprofen, for example, in addition to inhibiting the expected COX products, LOX and CYP products were also affected, but only in livers from male rats [74 ▪ ]. Hence the use of drugs could be a significant source of variability.…”

Effects of conventionally treated and ozonated wastewater on the damselfly larva oxylipidome in response to on-site exposure

“…Interestingly, larvae exposed to effluent that also had been treated with ozone did not show any reduction of 12 (13)-EpODE but the reduction of 15(16)-EpODE still remained. Fatty acid epoxides are formed by CYP epoxygenase enzymes and have been previously found to be affected in mice treated with the NSAID ibuprofen (Tiwari et al, 2021). NSAIDs are commonly present in WWTP effluents, e.g., diclofenac was measured in the effluent of this study, and thus could potentially cause the observed reduction of fatty acid epoxides in damselfly larvae exposed to WWTP effluents, however little is Fig.…”

Detoxification Cytochrome P450s (CYPs) in Families 1–3 Produce Functional Oxylipins from Polyunsaturated Fatty Acids

“…For example, DiHODE concentrations in hyperlipidemic men were decreased compared to normolipidemic men [156], but no follow up on this study has been completed. EpODE concentrations have been shown to be significantly increased in male rats upon treatment with ibuprofen [157]; however, the cause or effects of this change in oxylipin profile have yet to be investigated. Several of these oxylipins have been associated with pregnancy and gestation.…”