Variation in P450 oxidoreductase (POR) A503V and flavin-containing monooxygenase (FMO)-3 E158K is associated with minor alterations in nicotine metabolism, but does not alter cigarette consumption

Abstract

Nicotine metabolism rates differ widely, even after controlling for genetic variation in the major nicotine metabolizing enzyme, CYP2A6. Genetic variants in an additional nicotine metabolizing enzyme, flavin containing monooxygenase (FMO)-3, and an obligate microsomal CYP-supportive enzyme, cytochrome P450 oxidoreductase (POR), were investigated. We examined the impact of FMO3 E158K and POR A503V, before and after stratifying by CYP2A6 metabolism group. In 130 non-smokers of African descent who received 4 mg oral nicotine, FMO3 158K trended towards slower nicotine metabolism in reduced CYP2A6 metabolizers (P=0.07) only, whereas POR 503V was associated with faster CYP2A6 activity (nicotine metabolite ratio) in normal (P=0.03), but not reduced, CYP2A6 metabolizers. Neither FMO3 158K nor POR 503V significantly altered the nicotine metabolic ratio (N=659), cigarette consumption (N=667), or urine total nicotine equivalents (N=418) in smokers of African descent. Thus, FMO3 E158K and POR A503V are minor sources of nicotine metabolism variation, insufficient to appreciably alter smoking.

Predictors of Variation in CYP2A6 mRNA, Protein, and Enzyme Activity in a Human Liver Bank: Influence of Genetic and Nongenetic Factors

“…**P , 0.01, ***P , 0.001, on the basis of Mann Whitney tests. (Gomes et al, 2009;Chenoweth et al, 2014b;Lv et al, 2016), we investigated the association of three POR SNPs (rs17148944, rs2868177, rs1057868) with POR mRNA expression, POR protein levels, and, owing to the observed association between POR protein and CYP2A6 activity, with CYP2A6 enzyme activity. POR SNP rs2868177 was associated with higher POR mRNA expression (AA, AG, GG genotype means 5 202, 221, and 240 FPKM values, respectively, P , 0.05); however, there were no other associations between POR genotypes and POR and CYP2A6 phenotypes (P values provided in Supplemental Table 2).…”

“…has not yet been investigated. P450 oxidoreductase (POR), an enzyme that donates electrons to P450s during their catalytic cycle (Hu et al, 2012), also contributes to variation in multiple P450 activities, including those of CYP2A6 (Gomes et al, 2009;Chenoweth et al, 2014b;Lv et al, 2016).…”

“…Combined effects of CYP2A6, AKR1D1, and POR genetic variation should also be considered. POR SNP rs1057868 interacts with CYP2A6 genotype, with rs1057868 only associating with faster CYP2A6 activity among individuals not possessing known CYP2A6 reduced-function genetic variants (Chenoweth et al, 2014b). Owing to potential shared effects of each genetic factor on CYP2A6 activity, we aimed to elucidate both the independent and combined influences of CYP2A6, POR, and AKR1D1 genetic variation on CYP2A6 mRNA expression, protein levels, and enzyme activity.…”

Determination of Genetic Mechanisms Underlying Smoking Addiction

“…All have PhyloP Scores > 4 ( Table 3.2). Both ala 312 and ala 315 Other researchers have reported nominally significant association of CHRNA9 (rs4861065) with ND in a female Israeli sample 141 and of CHRNA9 (rs766988 and rs4861065) with response inhibition, as well as of CHRNA9 (rs4861065) with selective attention in a subset of the same sample, in which neurocognitive functions are putatively implicated in ND susceptibility. 142 Chikova et al 143 revealed that rs56159866 and rs6819385 in CHRNA9 are associated with an increased risk of lung cancer, while three SNPs, rs55998310, rs56291234, and rs182073550 (single nucleotide deletion) protect against lung cancer.…”

“…Smoking cessation OPRM1 Chenoweth et al 312 African 667 Nicotine metabolic ratio, CPD, nicotine equivalents in urine POR, FMO3 OPRM1 HD 355 Substance dependence (heroin/cocaine) 356 Antisocial drug dependence 344 Cocaine cue-reactivity 354 SLC6A4 HD 357 CD 37 * AD alcohol dependence; CD cocaine dependence; HD heroin dependence; ND nicotine dependence. 130 Chapter 5…”