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 (C 8 H 8 O 5 ) and 3-imino-6-methyl-2,3-dihydropran-2,4dione (C 6 H 5 O 3 N) 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.