Sex differences in CYP450-based sodium dehydroacetate metabolism and its metabolites in rats

Sodium dehydroacetate (DHA-Na), a widely used preservative, can induce sex-differentiated coagulation disorders primarily resulting from its metabolism. However, the underlying mechanisms remain poorly understood. Here, we identified several Cytochrome P450 (CYP450) sub-enzymes involved in sex differences related to DHA-Na metabolism, along with two related DHA-Na metabolites. CYP1A2, CYP3A2, and CYP2D1 were primarily responsible for DHA-Na metabolism, which was stronger in male rats than in female rats. Inhibition of these isoforms separately resulted in the DHA-Na metabolic capacity in male rats becoming equal to, or even weaker than, that in female rats. Furthermore, Cyp1a2, Cyp3a2, Cyp2d1, and Cyp2c11 expression was higher in male rats than in female rats, suggesting these enzymes are related to exhibited sex differences in DHA-Na metabolism. Moreover, 3-glycoloyl-6-methy-2,3-dihydropyran-2,4-dione (C₈H₈O₅) and 3-imino-6-methyl-2,3-dihydropran-2,4dione (C₆H₅O₃N) were identified as the two main DHA-Na metabolites. These findings provide crucial insights into potential mechanisms underlying sex differences in DHA-Na metabolism and its metabolites in rats.