Inhibition of cytochrome P450 6D1 by alkynylarenes, methylenedioxyarenes, and other substituted aromatics

We evaluated 33 compounds, comprising five different structural groups (alk ynylpyrenes, alkynylphenanthrenes, methylenedioxyarenes, flavones, and misc ellaneous), as inhibitors of house fly P450 6D1 (CYP6D1). In general, alkyn ylpyrenes were the most potent group of inhibitors, with maximum effectiven ess noted when the substituent was in the 4 position. Substituted phenanthr enes were reasonable CYP6D1 inhibitors with the lowest IC50 observed for th e analogue with the methylenedioxy substituent between the 9 and 10 positio ns. The 10 methylenedioxyarenes varied considerably in their ability to inh ibit CYP6D1. Piperonyl butoxide was the most potent inhibitor with increasi ng length of the alkyl substituent resulting in decreasing inhibition. Kara njin had the lowest IC50 of the 4 flavones that were tested. Overall, the m ost potent CYP6D1 inhibitors were large planar compounds. Four inhibitors w ere evaluated as permethrin synergists in the LPR strain of house fly (perm ethrin is detoxified via CYP6D1 in this strain) and they increased permethr in toxicity by 16- to 83-fold. The effect of structure on inhibition potenc y, as well as the mechanism of inhibition for seven representative inhibito rs, is discussed. (C) 2000 Academic Press.