Metabolic map of osthole and its effect on lipids

Abstract

<p>1. Osthole, a coumarin compound from plants, is a promising agent for the treatment of metabolic diseases, including hyperglycemia, fatty liver, and cancers. Studies indicate that the peroxisome proliferator-activated receptors (PPAR) α and γ are involved in the pharmacological effects of osthole. The <i>in vitro</i> and <i>in vivo</i> metabolism of osthole and its biological activity are not completely understood.</p> <p>2. In this study, ultra-performance chromatography electrospray ionization quadrupole time-of-flight mass spectrometry (UPLC–ESI–QTOFMS)-based metabolomics was used to determine the metabolic pathway of osthole and its influence on the levels of endogenous metabolites. Forty-one osthole metabolites, including 23 novel metabolites, were identified and structurally elucidated from its metabolism <i>in vitro</i> and <i>in vivo</i>. Recombinant cytochrome P450s (CYPs) screening showed that CYP3A4 and CYP3A5 were the primary enzymes contributing to osthole metabolism.</p> <p>3. More importantly, osthole was able to decrease the levels of lysophosphatidylethanolamine (LPE) and lysophosphatidylcholine (LPC) in the plasma, which explains in part its modulatory effects on metabolic diseases.</p> <p>4. This study gives the insights about the metabolic pathways of osthole <i>in vivo</i>, including hydroxylation, glucuronidation, and sulfation. Furthermore, the levels of the lipids regulated by osthole indicated its potential effects on adipogenesis. These data contribute to the understanding of the disposition and pharmacological activity of osthole <i>in vivo</i>.</p