Zakhari S. Alcohol metabolism and epigenetics changes. Alcohol Research: Current Reviews 2013;35:9-16.
Metabolites, including those generated during ethanol metabolism, can impact disease states by binding to transcription factors and/or modifying chromatin structure, thereby altering gene expression patterns. For example, the activities of enzymes involved in epigenetic modifications such as DNA and histone methylation and histone acetylation, are influenced by the levels of metabolites such as nicotinamide adenine dinucleotide (NAD), adenosine triphosphate (ATP), and S-adenosylmethionine (SAM).
Chronic alcohol consumption leads to significant reductions in SAM levels, thereby contributing to DNA hypomethylation. Similarly, ethanol metabolism alters the ratio of NAD+ to reduced NAD (NADH) and promotes the formation of reactive oxygen species and acetate, all of which impact epigenetic regulatory mechanisms.
In addition to altered carbohydrate metabolism, induction of cell death, and changes in mitochondrial permeability transition, these metabolism-related changes can lead to modulation of epigenetic regulation of gene expression. Understanding the nature of these epigenetic changes will help researchers design novel medications to treat or at least ameliorate alcohol-induced organ damage.
Background: Despite a huge amount of research over the past few decades, our knowledge about the genes that underlie most chronic diseases remains incomplete. With few exceptions (such as certain BrCa mutations and breast and ovarian cancer), our current data on genes are of limited value in predicting the development throughout life of cancer, hypertension and other cardiovascular diseases, and most other chronic diseases.
Even for alcohol-related diseases, it is not possible at present to determine how an individual person will respond over a lifetime to varying amounts of alcohol intake: not all heavy drinkers develop cirrhosis or upper aero-digestive cancers; not all moderate drinkers lower their risk of cardiovascular disease. While the underlying genetic pattern of a person undoubtedly plays a role in his/her health outcomes, environmental factors, including alcohol consumption, may modify the effects of genetically determined functions. It is no longer adequate to compare genes vs. environment as causes of disease, even if we know the full genotype of an individual. It is increasingly being shown that it is the combination of genes, environment, and their interaction that is important. Epigenetics is one aspect of the study of such interactions.
Epigenetics has been defined by The Shorter Oxford English Dictionary as “The branch of biology that deals with the effect of external influences on development.” Wikipedia expands the definition: “The study of heritable changes in gene activity which are not caused by changes in the DNA sequence. Unlike simple genetics based on changes to the DNA sequence (the genotype), the changes in gene expression or cellular phenotype of epigenetics have other causes. The term also refers to the changes themselves: functionally relevant changes to the genome that do not involve a change in the nucleotide sequence.”
The present paper by Zakhari provides key insights into mechanistic effects of alcohol that could be of importance in understanding alcohol-related diseases, describing how alcohol may lead to either the expression of genetically determined functions or the suppression of such functions. Such information could potentially lead to interventions that might decrease the risk of certain diseases related to heavy alcohol consumption.
The Forum notes that Dr Zakhari, who has been for many years a leading scientist at the National Institute on Alcohol Abuse and Alcoholism (NIAAA), is now a senior executive at an organization supported by the beverage industry. However, this excellent paper reflects his work at NIAAA and deals specifically with mechanisms by which excessive alcohol may increase the risk of a number of alcohol-related diseases. The nature of this paper, in the opinion of the Forum, makes it unlikely that it could be biased in any ways that would favour the beverage industry.
Comments on the present paper: Overall, Forum reviewers were favorably impressed by this paper, which they thought provides important new data on potential mechanisms by which specific genetic factors may be modified (either enhanced or suppressed) by alcohol consumption. The paper focuses particularly on mechanisms that may relate to the adverse health consequences of heavy alcohol consumption. (A similar approach might be useful in evaluating the beneficial health aspects associated with moderate drinking.)
An interesting recent paper on methodology (Maldonado G. Toward a clearer understanding of causal concepts in epidemiology. Annals of Epidemiology 2013;23:743e749) emphasizes the difficulty one has in determining causality of diseases because of individual variability in susceptibility. For example, if all subjects in a study are genetically protected from getting cancer, the effect of any amount of alcohol would show no relation with this disease. On the other hand, if the population were enriched with genetically susceptible subjects, alcohol might show a large influence on the occurrence of cancer.
Unfortunately we are, at present, largely unable to account for individual susceptibility to disease in epidemiologic studies of the population. As has been emphasized by Forum member Van Velden, the more we learn about genetic factors underlying any health outcome, the more likely it will be that our epidemiologic studies may contribute to determining causality of diseases. The approach described by Zakhari in the present paper may also help us interpret studies of alcohol and health.
Stated reviewer Van Velden: “This is an important paper that describes the molecular basis of alcohol metabolism, and adds to the understanding of the nature of the epigenetic changes induced by ethanol metabolism. This will help researchers to design model medications to treat or at least ameliorate alcohol-related organ damage.” He added: “However, it is at this stage premature to use this information in clinical practice. Nutrigenetics will in the future play an increasingly important role in the management of diseases resulting from environmental influence such as diet.” Stated member Skovenborg: “We must be cautious about these findings: fine theories have often proved to be of little practical consequence in real-life situations and when tested in prospective randomized trials.”
Reveiwer Ursini wrote: “This review article by Zakhari is well written and organized. (For sure I’ll use it for teaching.) However, it does not provide a straightforward insight into the health effects of ethanol that can be used to support a statement in favor or against alcohol consumption. My point is that describing pathways and mechanisms does not necessarily mean that these pathways are activated in vivo in the same direction as those observed in experimental conditions. Nevertheless, knowing that these pathways exist will positively drive the attention of scientists to innovative approaches in both basic science and epidemiology. There are feedback mechanisms, adaptive mechanisms, rebounds, etc., that can produce in vivo effects just opposite to those observed. In this respect, the dose of alcohol is crucial.”
Ursini continued: “In conclusion, these kind of basic studies are fully sound in medical terms when in agreement with well-conducted epidemiological analyses. The consensus between the two fully different approaches is the only way to generate sound conclusions.”
Comments on this paper were provided by the following members of the International Scientific Forum on Alcohol Research:
Fulvio Ursini, MD, Dept. of Biological Chemistry, University of Padova, Padova, Italy
David Van Velden, MD, Dept. of Pathology, Stellenbosch University, Stellenbosch, South Africa
Harvey Finkel, MD, Hematology/Oncology, Boston University Medical Center, Boston, MA, USA
Erik Skovenborg, MD, Scandinavian Medical Alcohol Board, Practitioner, Aarhus, Denmark
Yuqing Zhang, MD, DSc, Epidemiology, Boston University School of Medicine, Boston, MA, USA
Arne Svilaas, MD, PhD, general practice and lipidology, Oslo University Hospital, Oslo, Norway
R. Curtis Ellison, MD, Section of Preventive Medicine & Epidemiology, Boston University School of Medicine, Boston, MA, USA
An additional critique from Benett Issi, of the Department of Cardiovascular Science, Leuven University, Belgium is available from bu.edu/alcohol-forum/www-bu-edualcohol-forumcritique-130/