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Interpatient Variability: Genetic Predisposition and Other Genetic Factors
Author(s) -
West William L.,
Knight Enid M.,
Pradhan Sikta,
Hinds Tanya S.
Publication year - 1997
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1002/j.1552-4604.1997.tb04347.x
Subject(s) - enzyme , xenobiotic , metabolite , drug metabolism , isozyme , metabolism , prodrug , biochemistry , biology , metabolic pathway , genetic variability , cytochrome p450 , glutathione , pharmacogenetics , polymorphism (computer science) , genetics , chemistry , gene , allele , genotype
Polymorphisms and other genetic factors related to enzymes metabolizing drugs and xenobiotic chemicals are well known. This article focuses on selected molecular mechanisms and introduces some of the clinical implications arising from genetically determined interpatient variability or expression in some of these enzymes. Selected are the polymorphic enzymes of cytochromes P‐450 (CYP) as examples of phase I enzymes and methyl transferases, n‐acetyl transferases, and glutathione‐s‐transferases as examples of phase II enzymes. The polymorphism surrounding arylhydrocarbon hydroxylase induction is briefly described. Phase I enzymatic reactions are predominantly oxidative, whereas phase II reactions often couple with the byproducts of phase I. Overall, in poor metabolizers, whether phase I or phase II, there is limited metabolism in most patients unless another major metabolic pathway involving other enzymes exists. Drug metabolism also depends on whether the parent compound is a prodrug that forms an active metabolite, and poor metabolizers under this condition will form only trace amounts of an active compound. Therefore, the clinical significance of genetic polymorphisms and other genetic factors may be related to substrate, metabolite, or the major elimination pathway.