Influence of <i>CYP2D6</i> Deletion, Multiplication, <i>–1584C</i>→<i>G</i>, <i>31G</i>→<i>A</i> and <i>2988G</i>→<i>A</i> Gene Polymorphisms on Dextromethorphan Metabolism among Mexican Tepehuanos and Mestizos

Abstract

The aim of this study was to explain the variability of CYP2D6 activity by the identification of CYP2D6 deletion and multiplications, and the single-nucleotide polymorphisms (SNPs) –1584C→G, 31G→A and 2988G→A in Mexican Mestizo and Tepehuano subjects. One hundred twelve Mestizos and 99 Tepehuano Amerindians were studied, who were previously phenotyped with dextromethorphan. The frequencies of CYP2D6*2A [–1584C→G] and *35 [–1584C→G, 31G→A] were 10.7 and 4.1%, respectively, in Mestizos, which is evidently a trend towards an extensive metabolism in carriers of the –1584G change. In Tepehuanos, *2A was identified with a frequency of 20%, and the allele *35 was not found. The frequencies of CYP2D6*5 (deletion) and *41[2988G→A] were 1.3 and 2.2% in Mestizos and 0.5 and 1% in Tepehuanos, respectively. The SNP 2988A was found to be significantly related with the intermediate metabolizer phenotype in Mestizos (R = 0.309; n = 88; p = 0.006). The multiplications had frequencies of 4.1% in Mestizos and 1.5% in Tepehuanos. Only in the Mestizos did the presence of multiplications significantly decrease the DM/DX (dextromethorphan/dextrorphan) values (R = 0.273; n = 88; p = 0.016). The polymorphisms studied had different frequencies between Tepehuanos and Mestizos (p < 0.001); however, in the Tepehuano group these had a low influence on their phenotypic expression. It helps to understand the genotype-phenotype relationships of CYP2D6 in our studied populations.

Distribution of CYP2D6 and CYP2C19 Polymorphisms Associated with Poor Metabolizer Phenotype in Five Amerindian Groups and Western Mestizos from Mexico

“…CYP2D6 alleles CYP2D6*2, *3, *4, *5, *10, and *17 in Mestizos from Mexico City display a frequency of 19.3%, 1.4%, 11.2%, 2.6%, 12.4%, and 1.6%, respectively (Lopez et al, 2005). In Mestizos from Durango (Northwest), alleles CYP2D6*2, *3, *4, *5, and *10 were reported, with frequencies of 10.7%, 0.9%, 13.1%, 1.3%, and 2.3%, respectively, in addition to 6.8% of PM phenotypes, similar to those reported in Caucasians (10%) (Sosa-Macias et al, 2006;Sosa-Macias et al, 2010). In Mexican-Amerindian groups, this information is more limited; during the search for CYP2D6*3, *4, *6, and *10 in Tepehuanos from Durango (Northwest, Mexico), only CYP2D6*4 was found at a low frequency (0.6%), suggesting that the PM phenotype is absent in this Amerindian group (Sosa-Macias et al, 2006).…”

CYP2D6 genotype and dextromethorphan hydroxylation phenotype in an Ecuadorian population

“…The frequency of null alleles (*3, *4, *4×N, *5, *6) in this study was higher than that in Chilean Mapuches [14] and Mexican Tepehuanos [15] (Table 2). Moreover, the * 1 x 2 /* 4 1 * 1 /* 1 * 1 /* 2 * 2 /* 2 * 1 /* 3 5 * 1 /* 1 0 * 1 /* 1 7 * 1 /* 2 9 * 1 /* 4 1 * 1 /* 3 * 1 /* 4 * 1 /* 4 x 2 * 1 /* 5 * 4 /* 1 0 * 5 /* 4 1 * 4 /* 4 frequency of reduced function alleles (*10, *17, *29, *41) in this population was similar to that reported in European populations, but lower than that in some Amerindian and African-American populations, and the frequency of duplication/multiplication of active CYP2D6 alleles was similar to the values reported for other South American and Amerindian populations (Table 2).…”

Evaluation of drug-metabolizing enzyme hydroxylation phenotypes in Hispanic populations: the CEIBA cocktail

“…On the contrary, the percentage of PMs in Ecuadorians (1%) was lower; moreover, no UMs were found in this Ecuadorian population, which is in agreement with previous findings in other Amerindian populations [66]. In the case of Amerindian populations of Mexican Tepehuano [9,67] and Panama Cuna [15,17], the percentage of PMs by using either dextromethorphan, or debrisoquine and sparteine, was null. However, among Ngawbe Amerindians from Panama, the percentage of PMs of debrisoquine and sparteine was 5.9% [18].…”