Sulfaphenazole

CYP2C9 is a major cytochrome P450 enzyme that is involved in the metabolic clearance of various therapeutic agents. Disruption of this enzyme’s activity can lead to adverse drug reactions.¹ Sulfaphenazole is an inhibitor of CYP2C9 (K_i = 0.3 μM) that demonstrates at least 100-fold selectivity over other CYP450 isoforms (K_is = 63 and 29 μM for CYP2C8 and CYP2C18, respectively, and no activity at CYP1A1, CYP1A2, CYP3A4, CYP2C19).^2,3 At 10 μM, sulfaphenazole has been shown to inhibit endothelium-derived hyperpolarizing factor synthase, a CYP450 isozyme in the porcine coronary artery homologous to CYP2C8/9 that generates reactive oxygen species in coronary endothelial cells and modulates vascular tone and homeostasis.⁴

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1. Rettie, A.E., and Jones, J.P. Clinical and toxicological relevance of CYP2C9: Drug-drug interactions and pharmacogenetics. Annu. Rev. Pharmacol. Toxicol. 45, 477-494 (2005).

2. Mancy, A., Dijols, S., Poli, S., et al. Interaction of sulfaphenazole derivatives with human liver cytochromes P450 ²C: Molecular origin of the specific inhibitory effects of sulfaphenazole on CYP 2C9 and consequences for the substrate binding site topology of CYP 2C9. Biochemistry 35(50), 16205-16212 (1996).

3. Sai, Y., Dai, R., Yang, T.J., et al. Assessment of specificity of eight chemical inhibitors using cDNA-expressed cytochromes P450. Xenobiotica 30(4), 327-343 (2000).

4. Fleming, I., Michaelis, U.R., Bredenkötter, D., et al. Endothelium-derived hyperpolarizing factor synthase (cytochrome P450 2C9) is a functionally significant source of reactive oxygen species in coronary arteries. Circ. Res. 88(1), 44-51 (2001).

Negoro, R., Tasaka, M., Deguchi, S., et al. Generation of HepG2 cells with high expression of multiple drug-metabolizing enzymes for drug discovery research using a PITCh system. Cells 11(10), 1677 (2022).