Xyloketal B, a marine compound, acts on a network of molecular proteins and regulates the activity and expression of rat cytochrome P450 3a: a bioinformatic and animal study

Su, Junhui; Chang, Cui; Xiang, Qi; Zhou, Zhi-Wei; Luo, Rong; Yang, Lun; He, Zhi-Xu; Yang, Hongtu; Li, Jianan; Bei, Yu; Xu, Jinmei; Zhang, Minjing; Zhang, Qihao; Su, Zhijian; Huang, Yadong; Pang, Jiyan; Zhou, Shu-Feng

XKB is a potent antioxidant with great potential for the treatment of CVD but its molecular targets and effects on drug-metabolizing enzymes remain unknown. 37 Human CYP3A is a major CYP subfamily that metabolizes over 60% of endogenous and exogenous materials. 6 Modulation of the activity and expression of CYP3A would cause substantial changes in drug metabolism in the clinical setting. In the present study, we predicted over 324 molecular targets and 61 related signaling pathways regulated by XKB. We found that XKB interacted with the rat hepatic Cyp3a2 homology model via hydrogen bond formation. Further, we found that XKB increased the AUC 0-t and C max of midazolam, and inhibited the activity and expression level of Cyp3a in rats treated with XKB for 8 days. Our findings indicate that the beneficial effects of XKB can be attributed to regulation of a network of molecular targets and signaling pathways and that XKB can regulate Cyp3a-mediated drug metabolism by suppressing the activity and expression of Cyp3a in vivo. Bioinformatic approaches have become a valuable way of predicting the interactome of a chemical molecule, so we used a DDI-CPI tool to predict the potential targets and employed DAVID to analyze the molecular targets and related signaling pathways regulated by XKB. Our findings show that XKB can modulate a number of functional proteins and related signaling pathways. These proteins and signaling pathways have important roles in the regulation of redox homeostasis, cell proliferation, apoptosis, energy metabolism, metabolism of xenobiotics, lipid and carbohydrate metabolism, and the inflammatory response. Interestingly, XKB shared a number of molecular targets with probucol, which was initially developed as an antihyperlipidemic drug for the treatment of coronary artery diseases but was removed from the USA market in 1995 after it was found to prolong the QT interval. 33, 43 The overlapped molecular targets suggest that XKB can regulate the same targets and signaling pathways as probucol. Probucol has been reported to lower cholesterol levels in the blood by increasing the rate of low-density lipoprotein catabolism, inhibiting cholesterol synthesis, and delaying cholesterol absorption. 44 It is also a potent antioxidant that suppresses the oxidation of cholesterol in low-density lipoproteins. The cholesterol efflux regulatory protein ABCA1 is considered its main target. 45 As a natural marine compound, XKB may be a promising agent for the treatment of CVD when its potential cardiovascular side effects can be minimized or avoided. Notes: values are shown as the mean ± standard deviation, (n=5). Abbreviations: RSD, relative standard deviation; MDZ, midazolam.