Chem. Pharm. Bull.(オピニオン)

1. P-glycoprotein (P-gp/MDR1), one of the most clinically important transmembrane transporters in humans, is encoded by the ABCB1/MDR1 gene. Recent insights into the structural features of P-gp/MDR...

Structure, function and regulation of P-glycoprotein and its clinical relevance in drug disposition

Expression and function of efflux drug transporters in the intestine

Cytochrome P450 (CYP) 3A4 is the most abundant enzyme of CYPs in the liver and gut that metabolizes approximately 50% currently available drugs. A number of important drugs have been identified as substrates, inducers, and/or inhibitors of CYP3A4. The substrates of CYP3A4 considerably overlap with those of P-glycoprotein. Both CYP3A4 and P-glycoprotein are subject to inhibition and induction by a number of factors. Mechanism-based inhibition of CYP3A4 is characterized by NADPH-, time-, and concentration-dependent enzyme inactivation occurring when some xenobiotics or drugs are converted by CYPs to reactive metabolites. Such an inhibition of CYP3A4 is caused by chemical modification of the heme, the protein, or both as a result of covalent binding of modified heme to the protein. To date, the identified clinically important mechanism-based CYP3A4 inhibitors mainly include macrolide antibiotics (eg, clarithromycin and erythromycin), anti-HIV agents (eg, ritonavir and delavirdine), antidepressants (eg, fluoxetine and fluvoxamine), calcium channel blockers (eg, verapamil and diltiazem), steroids and their modulators (eg, gestodene and mifepristone), and several herbal and dietary components. The inactivation of CYP3A4 by drugs often causes unfavorable and long-lasting drug-drug interactions and probably fatal toxicity, depending on many factors associated with the enzyme, drugs, and the patients. Clinicians are encouraged to have a sound knowledge of drug-induced, mechanism-based CYP3A4 inhibition; take proper cautions, and perform close monitoring for possible drug interactions when using drugs that are mechanism-based CYP3A4 inhibitors. To minimize drug-drug interactions involving mechanism-based CYP3A4 inhibition, it is necessary to choose safe drug combination regimens, adjust drug dosages appropriately, and conduct therapeutic drug monitoring for drugs with narrow therapeutic indices.

Clinically important drug interactions potentially involving mechanism-based inhibition of cytochrome P450 3A4 and the role of therapeutic drug monitoring

Resistance to therapeutic drugs encompasses a diverse range of biological systems, which all have a human impact. From the relative simplicity of bacterial cells, fungi and protozoa to the complexity of human cancer cells, resistance has become problematic. Stated in its simplest terms, drug resistance decreases the chance of providing successful treatment against a plethora of diseases. Worryingly, it is a problem that is increasing, and consequently there is a pressing need to develop new and effective classes of drugs. This has provided a powerful stimulus in promoting research on drug resistance and, ultimately, it is hoped that this research will provide novel approaches that will allow the deliberate circumvention of well understood resistance mechanisms. A major mechanism of resistance in both microbes and cancer cells is the membrane protein-catalysed extrusion of drugs from the cell. Resistant cells exploit proton-driven antiporters and/or ATP-driven ABC (ATP-binding cassette) transporters to extrude cytotoxic drugs that usually enter the cell by passive diffusion. Although some of these drug efflux pumps transport specific substrates, many are transporters of multiple substrates. These multidrug pumps can often transport a variety of structurally unrelated hydrophobic compounds, ranging from dyes to lipids. If we are to nullify the effects of efflux-mediated drug resistance, we must first of all understand how these efflux pumps can accommodate a diverse range of compounds and, secondly, how conformational changes in these proteins are coupled to substrate translocation. These are key questions that must be addressed. In this review we report on the advances that have been made in understanding the structure and function of drug efflux pumps.

Structure and function of efflux pumps that confer resistance to drugs

Summary

Objective: A large number of structurally and functionally diverse compounds act as substrates or modulators of p-glycoprotein (p-gp). Some of them possess multiple drug resistance (MDR)-reversing activity, but only a small number of them have entered clinical study. In order to uncover the factors which exert a significant impact on the interaction between substrates/modulators and p-gp, we have performed structure–activity relationship (SAR) analyses, including molecular modelling, two-dimensional (2D) and three-dimensional (3D) parameter-frame-setting analysis, quantitative structure activity relationship (QSAR) analysis among substrates/modulators, as well as clinically promising MDR-reversing agents.



Methods:  The physicochemical parameters C log P, CMR and all regression equations were derived by using C log P version 4·0 and the latest CQSAR software, respectively. Molecular modelling and all other parameter calculations were performed by using HyperChem version 5·0 program, after geometry optimization and energy minimization using the AM1 semiempirical method.



Results:  SAR analyses indicate that MDR reversal activity is correlated with the lipophilicity (C log P), molecular weight (log Mw), longest chain (Nlc) of the molecule and the energy of the highest occupied orbital (Ehomo). In addition, the presence of a basic tertiary nitrogen atom in the structure is also an important contributor to p-gp inhibitory activity. Some separation in space is achieved for different subsets of p-gp substrates and inhibitors using Nlc, C log P and Ehomo as three independent parameters in the 3D-parameter-frame setting.



Conclusion:  A highly effective p-gp modulator candidate should possess a log P value of 2·92 or higher, 18-atom-long or longer molecular axis, and a high Ehomo value, as well as at least one tertiary basic nitrogen atom. The results obtained may be useful in explaining drug–p-gp interactions for different compounds, including drug interactions and the development of new MDR chemosensitizers.

Structure–activity relationship: analyses of p‐glycoprotein substrates and inhibitors

A literature survey was conducted on herbs, their preparations and ingredients with reported liver protection activities, in which a total of 274 different species and hundreds of active ingredients have been examined. These ingredients can be roughly classified into two categories according to their activities: (1) the main ingredients, such as silybin, osthole, coumarin, glycyrrhizin, saikosaponin A, schisandrin A, flavonoids; and (2) supporting substances, such as sugars, amino acids, resins, tannins and volatile oil. Among them, some active ingredients have hepatoprotective activities (e.g. anti-inflammatory, anticancer, antioxidant, immunomodulating and liver cirrhosis-regulating effects). Calculation of physicochemical parameters indicates that the main ingredients with negative and positive Elumo values possibly display their hepatoprotective effects through different mechanisms, such as antioxidative, anti-inflammatory and immunomodulating effects. As the combination of herbs may achieve some treatment effects synergistically and/or additively, it is common in Chinese medicine to use mixtures of various medicinal herbs with pharmacologically active compounds to have synergistic and/or additive effects, or to reduce harmful effects of some pharmacologically active compounds. In particular, the active compounds with Clog P around 2 are suitable for passive transport across membranes and accessible to the target sites. Thus, Elumo and Clog P values are good indicators among the calculated parameters. Seven different physicochemical parameters (MW, Clog P, CMR, μ, Ehomo, Elumo and Hf) and four major biological activities (antioxidant, anti-inflammatory, antiviral/antitumor and immunomodulating) are discussed in this review. It is hoped that the discussion may provide some leads in the development of new hepatoprotective drugs.

/pdf/a-survey-of-chinese-herbal-ingredients-with-liver-protection-4fzko6fxh4.pdf

A survey of Chinese herbal ingredients with liver protection activities

Summary

Background: From the deductive point of view, neurotransmitter receptors can be divided into categories such as cholinergic (muscarinic, nicotinic), adrenergic (α- and β-), dopaminergic, serotoninergic (5-HT1∼5-HT5), and histaminergic (H1 and H2). Selective agonists and antagonists of each receptor subtype can have specific useful therapeutic applications. For understanding the molecular mechanisms of action, an inductive method of analysis is useful.



Objective:  The aim of the present study is to examine the structure–activity relationships of agents acting on G-protein coupled receptors.



Method:  Representative sets of G-PCR agonists and antagonists were identified from the literature and Medline [P.M. Walsh (2003) Physicians’ desk reference; M.J. O'Neil (2001) The Merck index]. The molecular weight (MW), calculated logarithm of octanol/water partition coefficient (C log P) and molar refraction (CMR), dipole moment (DM), Elumo (the energy of the lowest unoccupied molecular orbital, a measure of the electron affinity of a molecule and its reactivity as an electrophile), Ehomo (the energy of the highest occupied molecular orbital, related to the ionization potential of a molecule, and its reactivity as a nucleophile), and the total number of hydrogen bonds (Hb) (donors and receptors), were chosen as molecular descriptors for SAR analyses.



Results:  The data suggest that not only do neurotransmitters share common structural features but their receptors belong to the same ensemble of G-protein coupled receptor with seven to eight transmembrane domains with their resultant dipoles in an antiparallel configuration. Moreover, the analysis indicates that the receptor exists in a dynamic equilibrium between the closed state and the open state. The energy needed to open the closed state is provided by the hydrolysis of GTP. A composite 3-D parameter frame setting of all the neurotransmitter agonists and antagonists are presented using MW, Hb and μ as independent variables.



Conclusion:  It appears that all neurotransmitters examined in this study operate by a similar mechanism with the G-protein coupled receptors.

G-protein coupled receptors: SAR analyses of neurotransmitters and antagonists.

In view of the increasing number of patients undergoing kidney dialysis or transplant every year, a survey of the literature on renal protective medicinal plants was undertaken. Most of them are from traditional Chinese medicine (TCM). Although many of the medicinal herbs reported have not been investigated in terms of active chemical ingredients, some do have compounds well characterized. They fall into a wide range of structures. Several groups of compounds with well established activities are discussed. These include: antioxidant phenolic compounds like tannins, flavonoids, isoflavonoids, unsaturated organic acids and lignans; circulation enhancing compounds like saponins, and basic alkaloids with multiple targets (G-protein coupled receptors). Also presented are proinflammatory and antiinflammatory fatty acids like linoleic (n-6) and α-linolenic (n-3) acids, respectively. Attention is also drawn to the plants containing nephrotoxic aristolochic acid. Different directions of future research are also presented. We hope that this review may provide some leads for new drug discovery and development, and more rational application of TCM.

/pdf/phytochemical-analysis-of-medicinal-plants-with-kidney-12rv65ny0m.pdf

Phytochemical analysis of medicinal plants with kidney protective activities

During the course of our investigation of longevity promoting natural products and Chinese herbs in the last 15 years, we come to the conclusion that in order to have healthy, productive and graceful maturing, it is necessary to maintain a dynamic balance between proinflammatory and anti-inflammatory loads. This may also help to prevent cancer as well as premature degeneration of various organ systems. Modern life style and food intake tend to overload proinflammatory factors. To overcome this it is desirable to regularly consume fresh fruits, vegetables and multiple grains, various beans including soybeans and/or minimally processed, unbleached products. When this is not sufficient or possible, taking proper dietary supplements under the guidance of knowledgeable health professional can be helpful.

Linda Lin-min Lien

Papers

Structure–activity relationship: analyses of p‐glycoprotein substrates and inhibitors

A survey of Chinese herbal ingredients with liver protection activities

G-protein coupled receptors: SAR analyses of neurotransmitters and antagonists.

Phytochemical analysis of medicinal plants with kidney protective activities

Longevity depends on a balance between proinflammatory and anti-inflammatory factors: use of TCMS and natural products.