Inhibition and induction of human cytochrome P450 enzymes: current status.
Variability of drug metabolism, especially that of the most important phase I enzymes or cytochrome P450 (CYP) enzymes, is an important complicating factor in many areas of pharmacology and toxicology, in drug development, preclinical toxicity studies, clinical trials, drug therapy, environmental exposures and risk assessment. These frequently enormous consequences in mind, predictive and pre-emptying measures have been a top priority in both pharmacology and toxicology. This means the development of predictive in vitro approaches. The sound prediction is always based on the firm background of basic research on the phenomena of inhibition and induction and their underlying mechanisms; consequently the description of these aspects is the purpose of this review. We cover both inhibition and induction of CYP enzymes, always keeping in mind the basic mechanisms on which to build predictive and preventive in vitro approaches. Just because validation is an essential part of any in vitro-in vivo extrapolation scenario, we cover also necessary in vivo research and findings in order to provide a proper view to justify in vitro approaches and observations.
Pelkonen
Olavi
O
Department of Pharmacology and Toxicology, Institute of Biomedicine, University of Oulu, PO Box 5000 (Aapistie 5 B), 90014 Oulu, Finland. olavi.pelkonen@oulu.fi
Turpeinen
Miia
M
Hakkola
Jukka
J
Honkakoski
Paavo
P
Hukkanen
Janne
J
Raunio
Hannu
H
D000818:Animals; D001681:Biological Assay; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000737:chemistry; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004347:Drug Interactions; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007527:Isoenzymes; D007700:Kinetics; D008954:Models, Biological; D008956:Models, Chemical; D015394:Molecular Structure; D011487:Protein Conformation; D021281:Quantitative Structure-Activity Relationship; D015203:Reproducibility of Results; D013379:Substrate Specificity
D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D003577:Cytochrome P-450 Enzyme System