Assessment of CYP2C9, CYP2C19, and CYP2D6 Polymorphisms in Allergic Patients with Chemical Sensitivity

Abstract

Background: Self-reported chemical sensitivity (SCS) is characterized by adverse effects due to exposure to low levels of chemical substances. The clinical manifestations of SCS are similar to the allergy, and a high percentage of individuals with both diseases have been found. Various genes, especially genes of importance to the metabolism of xenobiotic compounds, have been associated with SCS. Objectives: The purpose of this study was to investigate whether allergic individuals with chemical sensitivity differed from allergic patients without chemical sensitivity with regard to the distribution of genotype and phenotype of CYP2C9, CYP2C19, and CYP2D6 polymorphisms. Methods: A total of 180 patients were enrolled for this study. A questionnaire was employed to collect information on individual chemical sensitivity, while the Skin prick test and the PATCH test were used to verify the presence of an allergic condition against inhalants or contact allergens, respectively. For the evaluation of the CYP2C9, CYP2C19, and CYP2D6 polymorphisms, we used a strategy based on the amplification of the entire gene coupled to direct genomic DNA sequencing analysis. Results: Overall, a total of 15 different CYP2C9, CYP2C19, and CYP2D6 haplotypes were identified in our population. If the 5 CYP2C9 and the 2 CYP2C19 identified alleles correspond to the previously described ones, 4 of the 8 CYP2D6 haplotypes, detected in the study group, present new SNPs combinations. These new suballeles were categorized as CYP2D6*2M Sa­lento Variant 1, CYP2D6*35B Salento Variant 2, CYP2D6*41 Salento Variant 3, and CYP2D6*4P Salento Variant 4 due to the presence of the key SNPs 2,850 C>T, 31G>A, 2,988 G>A, and 1,846 G>A, respectively. When the allergic individuals are divided into 2 groups according to their SCS score, we observed that the distribution of the CYP2D6 phenotypes was significantly different between the 2 groups. Conclusions: Our idea is that the application of the questionnaire that we have adopted has enabled us to diagnose a degree of chemical sensitivity, which results as comorbid of the allergic disease and in which a condition of poor or intermediate metabolizes for the detrimental CYP2D6 alleles, could represent a discriminant between the chemical sensitivity and the health state.

Genetic and phenotypic frequency distribution of CYP2C9, CYP2C19 and CYP2D6 in over 3200 Han Chinese

“…As stressed by the US Food and Drug Administration (FDA), as well as other pharmacogenetic (PGx) guideline‐formulating agencies, such as the Clinical Pharmacogenetics Implementation Consortium (CPIC), Canadian Pharmacogenomics Network for Drug Safety (CPNDS), Dutch Pharmacogenetics Working Group (DPWG) and French National Network (Réseau) of Pharmacogenetics, most of the genetic polymorphisms that influence drug responses are related to P450 metabolic enzymes 2 . Of these variations in P450 metabolic enzymes, the genetic polymorphisms of CYP2C9, CYP2C19 and CYP2D6 have been the most thoroughly examined thus far 3 . There is still an ongoing debate, however, involving whether to guide clinical drug dosing based on the detection of these main PGx genes 4 .…”

Chemical Intolerance and Mast Cell Activation: A Suspicious Synchronicity

“…Targeted genetic association studies have focused on (a) inflammatory and oxidative stress pathways [23]; (b) genes coding for enzymes that metabolize xenobiotics (e.g., SOD, NAT) [24][25][26]; (c) genetic polymorphisms that involve xenobiotic detoxification processes such as phase I and II enzymes [27,28]; (d) cytochrome P450 isoenzymes involved in metabolizing drugs [29]; and (e) genes such as PON1/PON2 involved in the detoxification of organophosphate pesticides [26,30]. However, reports from other researchers have been inconsistent [23,31,32].…”

Olfactory-Related Quality of Life in Multiple Chemical Sensitivity: A Genetic-Acquired Factors Model

“…In this vision, many attempts-with different results-have been conducted in order to highlight the possible relationships between genetic polymorphisms and quality of life tests and to depict possible routes of pathophysiological models underpinning the development of MCS-related complaints. Among the vast literature regarding the gene polymorphisms involved in MCS, the overall approach is, at least, to define the individual genetic profiles of enzymes involved in body detoxification from xenobiotics such as phase I metabolism cytochrome P450 monoxygenases (CYP450), phase II metabolism glutathione-S-transferase (GST) and N-acetyl-transferase (NAT2), antioxidant defense, namely mitochondrial superoxide dismutase (SOD2), paraoxonase 1 and 2 (PON1, PON2), endothelial and inducible nitric oxide synthase (NOS2, NOS3) as well as folate cycle/methylation (MTHFR) [10,31,[39][40][41][42][43][44][45][46]. The hypothesis underlying the above cited investigations was the fact that the extreme individual sensitivity in MCS patients could be related to the inherited impairment in xenobiotics/endobiotics metabolism and to a vicious cycle [47] including peroxynitrite overproduction and lipid peroxidation, possibly not coped by the impairment in SOD, catalase, glutathione peroxidase, and NOS enzyme activities [48].…”