Pharmacogenetics of drug-metabolizing enzymes: implications for a safer and more effective drug therapy.
The majority of phase I- and phase II-dependent drug metabolism is carried out by polymorphic enzymes which can cause abolished, quantitatively or qualitatively decreased or enhanced drug metabolism. Several examples exist where subjects carrying certain alleles do not benefit from drug therapy due to ultrarapid metabolism caused by multiple genes or by induction of gene expression or, alternatively, suffer from adverse effects of the drug treatment due to the presence of defective alleles. It is likely that future predictive genotyping for such enzymes might benefit 15-25% of drug treatments, and thereby allow prevention of adverse drug reactions and causalities, and thus improve the health of a significant fraction of the patients. However, it will take time before this will be a reality within the clinic. We describe some important aspects in the field with emphasis on cytochrome P450 and discuss also polymorphic aspects of foetal expression of CYP3A5 and CYP3A7.
Ingelman-Sundberg
Magnus
M
Division of Molecular Toxicology, IMM, Karolinska Institutet, Nobels väg 13, 171 77 Stockholm, Sweden. maging@ki.se
Rodriguez-Antona
Cristina
C
D000595:Amino Acid Sequence; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism; D001483:Base Sequence; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D030541:Databases, Genetic; D004358:Drug Therapy / Q000379:methods*; D004798:Enzymes / Q000235:genetics / Q000493:pharmacokinetics*; D005333:Fetus / Q000378:metabolism; D040461:Gene Components; D006801:Humans; D008658:Inactivation, Metabolic / Q000502:physiology; D008969:Molecular Sequence Data; D010597:Pharmacogenetics / Q000379:methods / Q000639:trends*; D011110:Polymorphism, Genetic
D004798:Enzymes; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; C104464:CYP3A protein, human; C510164:CYP3A5 protein, human; C103123:CYP3A7 protein, human; D051544:Cytochrome P-450 CYP3A