Inhibition of Cytochrome P450 6D1 by Alkynylarenes, Methylenedioxyarenes, and Other Substituted Aromatics

We evaluated 33 compounds, comprising five different structural groups (alkynylpyrenes, alkynylphenanthrenes, methylenedioxyarenes, flavones, and miscellaneous), as inhibitors of house fly P450 6D1 (CYP6D1). In general, alkynylpyrenes were the most potent group of inhibitors, with maximum effectiveness noted when the substituent was in the 4 position. Substituted phenanthrenes were reasonable CYP6D1 inhibitors with the lowest IC50 observed for the analogue with the methylenedioxy substituent between the 9 and 10 positions. The 10 methylenedioxyarenes varied considerably in their ability to inhibit CYP6D1. Piperonyl butoxide was the most potent inhibitor with increasing length of the alkyl substituent resulting in decreasing inhibition. Karanjin had the lowest IC50 of the 4 flavones that were tested. Overall, the most potent CYP6D1 inhibitors were large planar compounds. Four inhibitors were evaluated as permethrin synergists in the LPR strain of house fly (permethrin is detoxified via CYP6D1 in this strain) and they increased permethrin toxicity by 16- to 83-fold. The effect of structure on inhibition potency, as well as the mechanism of inhibition for seven representative inhibitors, is discussed.