Factors influencing rates and clearance in P450-mediated reactions: QSARs for substrates of the xenobiotic-metabolizing hepatic microsomal P450s.

Various contributory factors associated with the kinetics of cytochrome P450-mediated catalytic activity and the metabolic clearance of drug substrates are discussed and evaluated, based on literature data and physicochemical parameters. Quantitative relationships between molecular structure and biological activity for several series of P450 substrates are presented which point to certain commonalities in P450-catalyzed reactions. In particular, it appears that frontier orbital energies are especially important for the estimation of reaction rates and clearance for many P450 substrates, although occasionally these have to be combined with other descriptors, such as compound lipophilicity (in the form of logP or logD(74)).

[1]  D. Lewis,et al.  Cytochromes P450, Oxygen, and Evolution , 2001, TheScientificWorldJournal.

[2]  D. F. Lewis.  Frontier orbitals in chemical and biological activity: quantitative relationships and mechanistic implications. , 1999, Drug metabolism reviews.

[3]  D. Lewis,et al.  On the recognition of mammalian microsomal cytochrome P450 substrates and their characteristics: towards the prediction of human p450 substrate specificity and metabolism. , 2000, Biochemical pharmacology.

[4]  J. M. Pratt,et al.  The P450 catalytic cycle and oxygenation mechanism. , 1998, Drug metabolism reviews.

[5]  F. Guengerich,et al.  Cytochrome P-450 3A4: regulation and role in drug metabolism. , 1999, Annual review of pharmacology and toxicology.

[6]  Jeffrey P. Jones,et al.  Designing safer chemicals: predicting the rates of metabolism of halogenated alkanes. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[7]  D. Lewis,et al.  Cytochrome P450 Substrate Specificities, Substrate Structural Templates and Enzyme Active Site Geometries , 1999, Drug metabolism and drug interactions.

[8]  C. Hansch,et al.  QSAR of P450 oxidation: on the value of comparing kcat and km with kcat/km. , 1996, Drug metabolism reviews.

[9]  D. Smith,et al.  Species differences in metabolism and pharmacokinetics: are we close to an understanding? , 1991, Drug metabolism reviews.

[10]  A. Li,et al.  Substrates of human hepatic cytochrome P450 3A4. , 1995, Toxicology.

[11]  M H Tarbit,et al.  Structural determinants of cytochrome P450 substrate specificity, binding affinity and catalytic rate. , 1998, Chemico-biological interactions.

[12]  D. Lewis.  Homology modelling of human cytochromes P450 involved in xenobiotic metabolism and rationalization of substrate selectivity. , 1999, Experimental and toxicologic pathology : official journal of the Gesellschaft fur Toxikologische Pathologie.

[13]  Slobodan Petar Rendic,et al.  Human cytochrome P450 enzymes: a status report summarizing their reactions, substrates, inducers, and inhibitors. , 1997, Drug metabolism reviews.

[14]  C. Ioannides,et al.  A quantitative structure-activity relationship study on a series of 10 para-substituted toluenes binding to cytochrome P4502B4 (CYP2B4), and their hydroxylation rates. , 1995, Biochemical pharmacology.

[15]  D. Lewis,et al.  Quantitative structure-activity relationships in substrates, inducers, and inhibitors of cytochrome P4501 (CYP1). , 1997, Drug metabolism reviews.

[16]  D. Lewis,et al.  Structural characteristics of human P450s involved in drug metabolism: QSARs and lipophilicity profiles. , 2000, Toxicology.

[17]  D. Lewis,et al.  COMPACT: a structural approach to the modelling of cytochromes P450 and their interactions with xenobiotics , 2001 .

[18]  S. Ekins,et al.  Three-dimensional-quantitative structure activity relationship analysis of cytochrome P-450 3A4 substrates. , 1999, The Journal of pharmacology and experimental therapeutics.

[19]  D. Lewis,et al.  Interactions between redox partners in various cytochrome P450 systems: functional and structural aspects. , 2000, Biochimica et biophysica acta.

[20]  M H Tarbit,et al.  Molecular modelling of human CYP2E1 by homology with the CYP102 haemoprotein domain: investigation of the interactions of substrates and inhibitors within the putative active site of the human CYP2E1 isoform. , 2000, Xenobiotica; the fate of foreign compounds in biological systems.