Resveratrol, trans-3,5,4'-trihydroxystilbene, was first isolated in 1940 as a constituent of the roots of white hellebore (Veratrum grandiflorum O. Loes), but has since been found in various plants, including grapes, berries and peanuts. Besides cardioprotective effects, resveratrol exhibits anticancer properties, as suggested by its ability to suppress proliferation of a wide variety of tumor cells, including lymphoid and myeloid cancers; multiple myeloma; cancers of the breast, prostate, stomach, colon, pancreas, and thyroid; melanoma; head and neck squamous cell carcinoma; ovarian carcinoma; and cervical carcinoma. The growth-inhibitory effects of resveratrol are mediated through cell-cycle arrest; upregulation of p21Cip1/WAF1, p53 and Bax; down-regulation of survivin, cyclin D1, cyclin E, Bcl-2, Bcl-xL and clAPs; and activation of caspases. Resveratrol has been shown to suppress the activation of several transcription factors, including NF-kappaB, AP-1 and Egr-1; to inhibit protein kinases including IkappaBalpha kinase, JNK, MAPK, Akt, PKC, PKD and casein kinase II; and to down-regulate products of genes such as COX-2, 5-LOX, VEGF, IL-1, IL-6, IL-8, AR and PSA. These activities account for the suppression of angiogenesis by this stilbene. Resveratrol also has been shown to potentiate the apoptotic effects of cytokines (e.g., TRAIL), chemotherapeutic agents and gamma-radiation. Phamacokinetic studies revealed that the target organs of resveratrol are liver and kidney, where it is concentrated after absorption and is mainly converted to a sulfated form and a glucuronide conjugate. In vivo, resveratrol blocks the multistep process of carcinogenesis at various stages: it blocks carcinogen activation by inhibiting aryl hydrocarbon-induced CYP1A1 expression and activity, and suppresses tumor initiation, promotion and progression. Besides chemopreventive effects, resveratrol appears to exhibit therapeutic effects against cancer. Limited data in humans have revealed that resveratrol is pharmacologically quite safe. Currently, structural analogues of resveratrol with improved bioavailability are being pursued as potential therapeutic agents for cancer.

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Role of Resveratrol in Prevention and Therapy of Cancer: Preclinical and Clinical Studies

As the details of the chemical transformations in metabolism have become increasingly clear, and the enzymes catalysing many of the reactions have been characterized, it is understandable that biochemists should want to explain at the molecular level the metabolic homeostasis observed at the physiological level. How are the rates of synthesis and degradation of metabolites kept in close balance over a very wide range of external conditions without catastrophic rises or falls in the metabolite concentrations? The discoveries of feedback inhibition, co-operativity and covalent modification in enzymes, and of mechanisms for the control of enzyme synthesis and degradation, have disclosed a repertoire of molecular effects that potentially alter the fluxes in metabolic pathways. With such a range of effects to choose from, it is not surprising that disputes arise over explanations for the changes in flux through particular pathways under given circumstances. Since the explanations are usually verbal and qualitative, discrimination between different explanations, or assessment of their adequacy, is difficult. More recently, several groups have attempted theoretical analysis of the potential of these different molecular mechanisms to contribute to the control of metabolic flux. Since these theories can be given a mathematical formulation, they can be used in combination with appropriate experimental measurements to provide quantitative explanations and, potentially, predictions. The theories have often been controversial. Matters at issue have included the extent to which it is feasible to perform experiments to obtain the necessary data, the adequacy of the theories for making useful predictions, and the degree to which the quantitative measures of the theories do actually capture the relevant aspects of regulation and control. To some extent, this is a matter of semantics; a mathematical theory is more explicit about its underlying assumptions and the meaning of its statements, but regulation and control are two terms that have been used without strict adherence to any agreed definition in many different contexts (as noted in [1]). It is therefore inevitable that some will find that the use of these terms in the context of a mathematical theory places a narrower construction on them than they would like. These theories all include a form of sensitivity analysis; that is, the magnitude of the effect of some small change in a parameter (such as an enzyme activity) on a metabolic system property (such as the flux or the concentration of a metabolite) is mathematically related to the properties of the components of the system. Sensitivity analysis is widely used for analogous problems in other fields, including economics, ecology [2], engineering [3] and chemical kinetics [4-6]. Its application in biochemistry was pioneered by Higgins [7], but three variants subsequently arose: Metabolic Control Analysis, Biochemical Systems Theory and Crabtree and Newsholme's 'flux-oriented' theory (the term used in [8]). It is not possible to give a succinct account of the differences between the approaches, which is a controversial area [9-18] even though the underlying mathematics is equivalent to a considerable extent. One area of difference is the choice of the type of parameter that is changed for the determination of sensitivities. In Metabolic Control Analysis, enzyme concentration (or activity) is usually chosen; the response to an external modifier of a metabolic pathway is derived from the resulting sensitivities. In Biochemical Systems Theory [19-25], the primary parameters for the sensitivities are the 'rate constants' for synthesis and degradation of metabolite pools. Savageau has given many reasons for this choice of parameter; Cornish-Bowden has articulated some of the problems with it [15]. Although using these 'rate constants' simplifies the analysis procedures within Biochemical Systems Theory, there is not a one-to-one relationship between them and the enzymes of the system, which can create a slight complication in determining the sensitivity to variation of an enzyme activity. Savageau's theory is part of an integrated system for stability analysis and simulation, in addition to sensitivity analysis. Crabtree and Newsholme's theory [8,10,26-30] is intermediate between the two others, and the primary sensitivities are to an external modifier (a hypothetical one if necessary), but its mathematical development is less rigorous. In this review, I shall concentrate on Metabolic Control Analysis. This is because, apart from considerations of space, approximately two-thirds of the literature citations of theories of metabolic regulation in the past 5 years have been to Metabolic Control Analysis. This may relate to perceived ease of use, which has been compared using the different approaches on the same set of experimental results [31]. In the following review, I will not give a complete derivation and description of the basic concepts of Metabolic Control Analysis; clear accounts can be found in previous articles and reviews [9,32-39]. Instead I will try to indicate areas of disagreement, the scope of the basic theory and where it has been modified or extended, and recent approaches to experimental applications.

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Metabolic control analysis: a survey of its theoretical and experimental development.

The primary enzymes involved in alcohol metabolism are alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH). Both enzymes occur in several forms that are encoded by different genes; moreover, there are variants (i.e., alleles) of some of these genes that encode enzymes with different characteristics and which have different ethnic distributions. Which ADH or ALDH alleles a person carries influence his or her level of alcohol consumption and risk of alcoholism. Researchers to date primarily have studied coding variants in the ADH1B, ADH1C, and ALDH2 genes that are associated with altered kinetic properties of the resulting enzymes. For example, certain ADH1B and ADH1C alleles encode particularly active ADH enzymes, resulting in more rapid conversion of alcohol (i.e., ethanol) to acetaldehyde; these alleles have a protective effect on the risk of alcoholism. A variant of the ALDH2 gene encodes an essentially inactive ALDH enzyme, resulting in acetaldehyde accumulation and a protective effect. It is becoming clear that noncoding variants in both ADH and ALDH genes also may influence alcohol metabolism and, consequently, alcoholism risk; the specific nature and effects of these variants still need further study.

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The Genetics of Alcohol Metabolism: Role of Alcohol Dehydrogenase and Aldehyde Dehydrogenase Variants

Vitamin A (retinol) and provitamin A (β-carotene) are metabolized to specific retinoid derivatives which function in either vision or growth and development. The metabolite 11-cis-retinal functions in light absorption for vision in chordate and nonchordate animals, whereas all-trans-retinoic acid and 9-cis-retinoic acid function as ligands for nuclear retinoic acid receptors that regulate gene expression only in chordate animals. Investigation of retinoid metabolic pathways has resulted in the identification of numerous retinoid dehydrogenases that potentially contribute to metabolism of various retinoid isomers to produce active forms. These enzymes fall into three major families. Dehydrogenases catalyzing the reversible oxidation/reduction of retinol and retinal are members of either the alcohol dehydrogenase (ADH) or short-chain dehydrogenase/reductase (SDR) enzyme families, whereas dehydrogenases catalyzing the oxidation of retinal to retinoic acid are members of the aldehyde dehydrogenase (ALDH) family. Compilation of the known retinoid dehydrogenases indicates the existence of 17 nonorthologous forms: five ADHs, eight SDRs, and four ALDHs, eight of which are conserved in both mouse and human. Genetic studies indicate in vivo roles for two ADHs (ADH1 and ADH4), one SDR (RDH5), and two ALDHs (ALDH1 and RALDH2) all of which are conserved between humans and rodents. For several SDRs (RoDH1, RoDH4, CRAD1, and CRAD2) androgens rather than retinoids are the predominant substrates suggesting a function in androgen metabolism as well as retinoid metabolism.

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Families of retinoid dehydrogenases regulating vitamin A function

Aldehyde dehydrogenases (ALDHs) belong to a superfamily of enzymes that play a key role in the metabolism of aldehydes of both endogenous and exogenous derivation. The human ALDH superfamily comprises 19 isozymes that possess important physiological and toxicological functions. The ALDH1A subfamily plays a pivotal role in embryogenesis and development by mediating retinoic acid signaling. ALDH2, as a key enzyme that oxidizes acetaldehyde, is crucial for alcohol metabolism. ALDH1A1 and ALDH3A1 are lens and corneal crystallins, which are essential elements of the cellular defense mechanism against ultraviolet radiation-induced damage in ocular tissues. Many ALDH isozymes are important in oxidizing reactive aldehydes derived from lipid peroxidation and thereby help maintain cellular homeostasis. Increased expression and activity of ALDH isozymes have been reported in various human cancers and are associated with cancer relapse. As a direct consequence of their significant physiological and toxicological roles, inhibitors of the ALDH enzymes have been developed to treat human diseases. This review summarizes known ALDH inhibitors, their mechanisms of action, isozyme selectivity, potency, and clinical uses. The purpose of this review is to 1) establish the current status of pharmacological inhibition of the ALDHs, 2) provide a rationale for the continued development of ALDH isozyme-selective inhibitors, and 3) identify the challenges and potential therapeutic rewards associated with the creation of such agents.

Aldehyde Dehydrogenase Inhibitors: a Comprehensive Review of the Pharmacology, Mechanism of Action, Substrate Specificity, and Clinical Application

Sheep liver cytosolic aldehyde dehydrogenase: the structure reveals the basis for the retinal specificity of class 1 aldehyde dehydrogenases

Ethanol and acetaldehyde metabolism: past, present, and future.

Interaction of sheep liver cytosolic aldehyde dehydrogenase with quercetin, resveratrol and diethylstilbestrol.

The assessment of viability in isolated rat hepatocytes.

We used titration with the inhibitors tetramethylene sulphoxide and isobutyramide to assess quantitatively the importance of alcohol dehydrogenase in regulation of ethanol oxidation in rat hepatocytes. In hepatocytes isolated from starved rats the apparent Flux Control Coefficient (calculated assuming a single-substrate irreversible reaction with non-competitive inhibition) of alcohol dehydrogenase is 0.3-0.5. Adjustment of this coefficient to allow for alcohol dehydrogenase being a two-substrate reversible enzyme increases the value by 1.3-1.4-fold. The final value of the Flux Control Coefficient of 0.5-0.7 indicates that alcohol dehydrogenase is a major rate-determining enzyme, but that other factors also have a regulatory role. In hepatocytes from fed rats the Flux Control Coefficient for alcohol dehydrogenase decreases with increasing acetaldehyde concentration. This suggests that, as acetaldehyde concentrations rise, control of the pathway shifts from alcohol dehydrogenase to other enzymes, particularly aldehyde dehydrogenase. There is not a single rate-determining step for the ethanol metabolism pathway and control is shared among several steps.

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Kathryn E. Kitson

Papers

Sheep liver cytosolic aldehyde dehydrogenase: the structure reveals the basis for the retinal specificity of class 1 aldehyde dehydrogenases

Ethanol and acetaldehyde metabolism: past, present, and future.

Interaction of sheep liver cytosolic aldehyde dehydrogenase with quercetin, resveratrol and diethylstilbestrol.

The assessment of viability in isolated rat hepatocytes.

The importance of alcohol dehydrogenase in regulation of ethanol metabolism in rat liver cells