Effect of CYP2A6 Genetic Polymorphism on the Metabolic Conversion of Tegafur to 5-Fluorouracil and Its Enantioselectivity

Abstract

Tegafur (FT), a prodrug of 5-fluorouracil, is a chiral molecule, a racemate of R-and S-isomers, and CYP2A6 plays an important role in the enantioselective metabolism of FT in human liver microsomes (R-FT >> S-FT). This study examined the enantioselective metabolism of FT by microsomes prepared from Sf9 cells expressing wildtype CYP2A6 and its variants (CYP2A6*7, *8, *10, and *11) that are highly prevalent in the Asian population. We also investigated the metabolism of coumarin and nicotine, both CYP2A6 probe drugs, in these variants. Enzyme kinetic analyses showed that CYP2A6.7 (I471T) and CYP2A6.10 (I471T and R485L) had markedly lower V max values for both enantiomers than wild-type enzyme (CYP2A6.1) and other variant enzymes, whereas K m values were higher in most of the variant enzymes for both enantiomers than CYP2A6.1. The ratios of V max and K m values for R-FT to corresponding values for S-FT (R/S ratio) were similar among enzymes, indicating little difference in enantioselectivity among the wild-type and variant enzymes. Similarly, both CYP2A6.7 and CYP2A6.10 had markedly lower V max values for coumarin 7-hydroxylase and nicotine C-oxidase activities than CYP2A6.1 and other variant enzymes, whereas K m values were higher in most of the variant enzymes for both activities than CYP2A6.1. In conclusion, the amino acid substitutions in CYP2A6 variants generally resulted in lower affinity for substrates, while V max values were selectively reduced in CYP2A6.7 and CYP2A6.10. Consistent R/S ratios among CYP2A6.1 and variant enzymes indicated that the amino acid substitutions had little effect on enantioselectivity in the metabolism of FT.

Phase I study of orally administered S-1 in combination with epirubicin and oxaliplatin in patients with advanced solid tumors and chemotherapy-naïve advanced or metastatic esophagogastric cancer

“…The biological basis for this difference in the MTD of S-1 between different ethnic groups may, at least in part, be due to population differences in the genetic polymorphism status of the CYP2A6 gene, the product of which is a Objective response rate (CR ? PR), n (%) 0 0 3 (27) Evaluable for PFS n = 6 n = 4 n = 11 Events, n (%) principal enzyme in relation to the bioactivation of tegafur to 5-FU [25,29,30]. Suggestive of a high potential for tumor control, partial responses to EOS were seen in three (27 %) of 11 evaluable patients in cohort 3, and a further seven patients (64 %) had stable disease, including one patient with an unconfirmed partial response; only one patient (9 %) had progressive disease.…”

Biochemistry of nicotine metabolism and its relevance to lung cancer

“…Several of the other amino acid substitutions affect the kinetic parameters of nicotine 5'-oxidation. Among these the most significant impact is for I471T (CYP2A6*7) and V365M (CYP2A6*17), which have decreased intrinsic clearance of 83% and 69% respectively (125)(126)(127)(128). Notably, the closely related P450 2A13 has a methionine residue at position 365 and this change contributes to the larger active site of P450 2A13 compared to P450 2A6 and influences the binding of nicotine (67).…”

Genome-wide association meta-analysis of nicotine metabolism and cigarette consumption measures in smokers of European descent

“…This work will enhance NMR genomics for studies that include non-, former- and intermittent-smokers (as NMR can only be measured in current, regular smokers ( 7 )), for example in tobacco-related disease risk assessments ( 22 ), as well as in precision medicine approaches for smoking cessation ( 14 , 23 ) and for cancer due to the role of CYP2A6 in chemotherapeutic (e.g. letrozole, tegafur) drug metabolism ( 12 , 13 ).…”