The aryl hydrocarbon receptor ligands CAY10464 and CAY10465 are potent inhibitors of human CYP450 1A1, 1A2 and 1B1

Denis J Crankshaw, Cristina S Trambitas, Shirley Ho, Alison C Holloway. McMaster University, Hamilton, ON, Canada.

CAY10464 (1,3-dichloro-5-[(1E)-2-(4-methoxyphenyl)ethenyl]-benzene) and CAY10465 (1,3-dichloro-5-[(1E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-benzene) are analogues of resveratrol with selective activity at the aryl hydrocarbon receptor (AhR) (de Medina et al, 2005). We tested the hypothesis that, in common with several other AhR ligands, they would also be inhibitors of CYP450s of the 1 class. The ability of the compounds to inhibit the biotransformation of fluorogenic substrates by cDNA-expressed human CYP450 1A1, 1A2, 1B1, 2C19, 2D6 and 3A4 was examined by methods we have reported previously (Singh et al, 2008). The compounds had no effect on CYP450 2C19, 2D6 and 3A4 at concentrations up to 10 μM, but inhibited CYP450 1A1, 1A2 and 1B1 at submicromolar potencies as shown in the following table:

Both CAY10464 and CAY10465 are potent inhibitors of CYP450 1A1, 1A2 and 1B1 thus not all effects of these compounds should be ascribed to actions at the AhR.

De Medina P et al (2005) J Med Chem 48:287-291.
Singh M et al (2008) BPS winter meeting Abstract 116P.

Supported by SickKids Foundation & Canadian Institutes of Health Research.