CYP4F2*3 (V433M) Polymorphism Impacts Benzalkonium Chloride Metabolism in an Alkyl Chain Length-Dependent Manner

Abstract

<b>Abstract ID 53827</b> <b>Poster Board 426</b> Benzalkonium chlorides (BACs) are a class of quaternary ammonium compounds. They are among the most common active ingredients in disinfectants used in domestic cleaning, industrial processing, and clinical settings. BACs are primarily metabolized by cytochrome P450 (CYP) enzymes through ω-hydroxylation by CYPs 4F2 and 4F11 and (ω−1)-hydroxylation (or further internal oxidation) by CYPs 2D6 and 4F12. These primary metabolites are further metabolized to ω-carboxylic acid and (ω−1)-ketone products. We hypothesize that CYP polymorphism is a major determinant of inter-individual variability in BAC persistence in humans. CYP4F2 was previously found to be an ω–hydroxylase of C16 BAC, but not of C12 BAC. In this work, we investigated the impact of CYP4F2 polymorphism (*1/*1, *3/*3, and *1/*3) on C12 and C16 BAC metabolism in 4F2-genotyped and pooled (from 10 individuals for each genotype) human liver microsomes (HLM). Wild-type (WT) (<i>4F2*1/*1</i>) HLM exhibited a 2.08-fold higher metabolic rate for C16 BAC than <i>4F2*3/*3</i>; However, for C12 BAC, this ratio was only 1.09. The heterozygote (<i>4F2*1/*3</i>) HLM metabolic rates of both C12 and C16 BACs were close to WT, being 80% and 88% of the WT metabolic rates, respectively. The fraction metabolized (fm) of carboxylic acid for C16 BAC are 0.72 (*1/*1), 0.54 (*1/*3) and 0.22 (*3/*3), whereas for C12 BAC, this fm in all three variants are less than 0.05, suggesting CYP4F2 is a major contributor to the formation of ω-carboxylic acid from C16-BAC, but not C12-BAC. The use of the specific CYP2D6 inhibitor quinidine in all three groups of 4F2-genotyped HLM confirmed the significant contribution of CYP2D6 to (ω-1)-hydroxylation of both C16- and C12-BACs. Inhibition of CYP2D6 had a greater effect on C12 BAC metabolism than C16 BAC, reducing their (ω-1)-hydroxy metabolites by 67% and 55%, respectively, in WT HLM. In conclusion, the impact of <i>4F2*3</i> polymorphism on BAC metabolism in HLM was far greater for C16 BAC than for C12 BAC. Inhibition of 2D6 by quinidine was not necessary to observe this effect, indicating that the <i>4F2*3</i> polymorphism alone can substantially reduce C16 BAC metabolism in HLM. This study suggests that individuals with the CYP4F2 poor metabolizer genotype could be more susceptible to BAC exposure.