My previous attempt to raise this point was misdirected to the data on hydrophobic zone(s) in protein moiety of P-450 (CYP) influencing its active center’s substrate-binding and catalytic efficacy. In other words, membranous localization of monooxygenases is commonly ignored thus considering enzyme-kinetics of P450s as any other water-soluble enzymes. Inasmuch as the vast majority of modern medicines belonging to P45O substrates are relatively to highly lipophilic, and any pharnacy prescription drug information sheet contain data on drug-drug interactions, which occur at P450 active site, drugs' octanol-water partition coefficients (log P, by definition made by Hansch & Leo) values should be taken into calculations of Ks, Km, Vmax, Kcat, etc.
Nowadays, thirty years since we discussed the very point with Dr. Walter Pyerin of German Cancer Research Center, Heidelburg, his conclusions still sound very actual: “When the fluidity of the membrane was changed showing a well-defined gel to liquid crystalline phase transition, the activation energy of the monooxygenase reaction was changed at around the phase transition temperature, suggesting a conformational change of cytochrome P-450 caused by the fluidity change of the membrane. The incorporation of P-450 into liposomes was also found to affect the binding of substrates to cytochrome P-450. The decrease in the apparent dissociation constant of substrates upon incorporation into membranes suggests that the lipid membrane acts as a pool for hydrophobic substrates, which are concentrated in the lipid phase, and that cytochrome P-450 takes substrates directly from the membrane phase. Phospholipid membranes, therefore, play very important roles in various phases of the reaction of cytochrome P-450-dependent monooxygenase” (H. Taniguichi & W. Pyerin, Phospholipid bilayer membranes play decisive roles in the cytochrome P-450-dependent monooxygenase system. J Cancer Res Clin Oncol 114: 335-340, 1988).
I think you are right that logP (or logD for charged compounds) is relevant to the lipid-bound concentration of a substrate. However, it seems to me that there is a potential inaccuracy arising from equating octanol:water partition coefficient with biological membrane:aqueous environment partition coefficient. Is there a reliable method of measuring the concentration of substrate in the membrane in which the P450 enzyme is located? Moreover, one should also consider the possibility that the substrate in the membrane is not freely diffusible between the lipid phase and the enzyme's active site, so that the effective concentration is lower than the actual concentration.
Yes, Dr. Shapiro, there is almost perfect accuracy in approximation of octanol:water partition coefficient (logP) to distribution of a lipophilic P450 substrate between water compartment of the cell and its phospholipid-enriched endoplasmic reticulum membrane. It has been, alongside with others, shown, for a example, in our paper published in The Biochemical Journal, 160:75-83, 1976, in our survey: “Role of microsomal phospholipids in organizing and regulating the activity of a monooxygenase system” (Biological Reviews, 84:3-21, 1977), as well as in my (with Dr. Lyachovich) monograph entitled “Structural Aspects of Monooxygenases Biochemistry” (Science Press, NAUKA, 337 pp, 1978).
Since then, many data were published describing the crucial role of microsomal phospholipids in a substrate binding and metabolism at P450 (CYP) active site. Thus in Toxicol In Vitro.18(1):89-97, 2004, D. Lewis published a paper “Quantitative structure-activity relationships (QSARs) for substrates of human cytochromes P450 CYP2 family enzymes”, where substrate lipophilicity was determined of key importance to P450 binding affinity and enzyme selectivity. From an extensive compilation of log P values for P450 substrates, and by analysis of relationships between partitioning energy and substrate-binding free energy, the relevance of lipophilicity and other factors pertaining to P450 binding affinity was explained, leading to the formulation of lipophilicity relationships within substrates of each human P450 enzyme involved in drug metabolism. Furthermore, log P values for P450 substrates appear to represent markers for enzyme selectivity. Together with the important roles of hydrogen bonding and pi-pi stacking interaction energies, the desolvation of the P450 active site makes a major contribution to the overall substrate-binding energy.
LogP values become even of greater importance after revelation and dramatic developments (both in academic research and clinically-applied areas) of drug-drug interactions at CYP active site. Thus, among many recent data of others, Yi-Ting Zhou et al. presented a paper “Pharmacokinetic drug–drug interactions between 1,4-dihydropyridine calcium channel blockers and statins: factors determining interaction strength and relevant clinical risk management”, published in “Ther Clin Risk Manag. 10: 17–26, 2014). They studied phisico-chemical and enzyme kinetic parameters of coadministration of 1,4-dihydropyridine calcium channel blockers (DHP-CCBs) with statins reductase inhibitors, which is common for patients with hypercholesterolemia and hypertension. Authors investigated the inhibitory effects of 13 kinds of DHP-CCBs on human CYP-isoenzyme-dependent reactions using microsomes from human B-lymphoblast cells expressing CYP. Interestingly, lipophilicity was found to be an important factor in the strength of the pharmacokinetic interactions of DHP-CCBs. The logarithm of the molecular 1-octanol-water partition coefficient (logP) values indicated significant positive correlations with the interaction strength.
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