title: Influence of the genetic polymorphisms in the 5' flanking and exonic regions of CYP2C19 on proguanil oxidation.
abstract: CYP2C19 is a polymorphic enzyme which metabolizes several clinically important drugs including proguanil. Variation in the 5' regulatory region may influence CYP2C19 activity. This study evaluates the relationship between proguanil metabolic ratio and genetic variations of CYP2C19 in a South Indian population. Fifty unrelated healthy subjects were genotyped for CYP2C19 (*)2 and (*)3 alleles and the 5' flanking region of CYP2C19 was sequenced. Plasma concentrations of proguanil and cycloguanil were estimated by reverse phase HPLC after single oral doses (200 mg) of proguanil. In silico docking analysis of transcription factors binding to its sites in CYP2C19 5' regulatory region was performed. The mean metabolic ratios (proguanil/cycloguanil) were highest in (*)1/(*)2 or (*)1/(*)3 subjects and in (*)2/(*)2 or (*)2/(*)3 as compared to (*)1/(*)1 subjects. Subjects with promoter region variation -98T>C showed decrease in the metabolic ratios irrespective of other variation, which may explain the deviation from the genotype-phenotype association of CYP2C19. In silico analysis predicted alteration in the interaction of transcription factors to their binding sites in the presence of variant alleles. The results of this study would be useful in predicting interindividual differences in the metabolism of substrates of CYP2C19.
authors.affiliation: Pharmacogenomics Laboratory, Department of Pharmacology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Pondicherry 605006, India. uchakradhar@gmail.com
authors.forename: Chakradhara Rao Uppugunduri
authors.initials: CR
authors.lastname: Satyanarayana
authors.forename: Anichavezhi
authors.initials: A
authors.lastname: Devendran
authors.forename: Muthukumaran
authors.initials: M
authors.lastname: Jayaraman
authors.forename: Jayakanthan
authors.initials: J
authors.lastname: Mannu
authors.forename: Premendu P
authors.initials: PP
authors.lastname: Mathur
authors.forename: Shewade Deepak
authors.initials: SD
authors.lastname: Gopal
authors.forename: Krishnamoorthy
authors.initials: K
authors.lastname: Rajagopal
authors.forename: Adithan
authors.initials: A
authors.lastname: Chandrasekaran
mesh_terms: D024506:5' Flanking Region / Q000187:drug effects / Q000235:genetics*; D000818:Animals; D000962:Antimalarials / Q000097:blood / Q000494:pharmacology; D001189:Aryl Hydrocarbon Hydroxylases / Q000737:chemistry / Q000235:genetics*; D065731:Cytochrome P-450 CYP2C19; D004351:Drug Resistance / Q000235:genetics; D005091:Exons / Q000235:genetics; D006801:Humans; D009154:Mutation; D010100:Oxygen / Q000378:metabolism*; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D002727:Proguanil / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D000962:Antimalarials; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D002727:Proguanil; D010100:Oxygen