Modificări enzimatice în urma ingestiei cronice de alcool. consecințe în urma ingestiei cronice cu alcool

Introduction

Alcohol (ethyl-alcohol, ethanol) is together with nicotine one of the most abused, but nevertheless legal, substances. In 1999 each adult person (>15 y) in Switzerland consumed on average 11.45 L of pure alcohol consisting of 28% beer, 56% wine and 16% spirits. In 1998 the direct costs from alcohol consumption were at least 524 million sFr.31. The total costs caused by alcohol consumption are estimated to be about 6.5 billion sFr. a year11. In Switzerland only about 27% of women and 10% of men are complete teetotallers (all age groups), while 1% of women consume >40 g alcohol/d and 5% of men more than 60 g alcohol/d and are therefore considered to be abusers. The “limits” for alcohol abuse are gender specific because deleterious effects of alcohol tend to occur with a lower rate of consumption in women.

The illegal substances – the hard drugs like heroin, cocaine and ecstasy - are much more discussed in politics, but are far less used by the general population than alcohol.

The term “alcoholism" is not easily defined. The National Council on Alcoholism and Drug Dependence (USA) has proposed the following definition: “Alcoholism is a primary, chronic disease with genetic, psychosocial, and environmental factors influencing its development and manifestations. The disease is often progressive and fatal. It is characterized by continuous or periodic: impaired control over drinking, preoccupation with the drug alcohol, use of alcohol despite adverse consequences, and distortions in thinking, most notably denial”. Important is, that alcoholism is considered to be a disease that is classified as such as well in the 10th edition of the International Classification of Diseases (ICD 10) of the WHO as in the 4th Diagnostic and Statistica Manual for psychic diseases (DSM-IV) of the American Psychiatric Association.

Since there are many reasons for excessive drinking, varying susceptibilities, and different drinking patterns subclassifications have been proposed: Jellinek distinguished the way of, the dependence and the self-control in drinking. He described 5 different drinking types that experience distinguishable problem patterns. Cloninger proposed a simpler approach, only distinguishing 2 types. One is supposed to be related mostly to environmental factors, the other to genetic / hereditary factors. These types were refined by other authors with relation to the onset of the disease.

A beneficial effect of moderate alcohol consumption (e.g. one glass of wine or beer a day) has been well documented particularly in regard to cardiovascular function. In contrast, a consumption of >40 g/day in women and of >60 g/day in men over a prolonged period of time is associated with medical, social and psychic problems.

Clinical features and effects of alcohol vary with its concentrations. These signs are dependent on a number of factors including the rate of intake, the degree of individual tolerance and the nutritional status.

Due to its chemical properties (well soluble in water and fat) alcohol is readily absorbed from the stomach and small intestine. Already a few minutes after ingestion alcohol can be detected in blood. About 5-10% of an orally ingested dose are metabolised by ADH(Alcohol dehydrogenase) of the stomach. In addition to this gastric first pass effect which may vary considerably depending on the nutritional status of the subject, there is an equally variable hepatic first pass effect, so that only a fraction of an ingested amount of alcohol reaches the systemic circulation. Most of the metabolism of alcohol occurs in the liver. Approximately 5-10% are excreted unchanged via the lungs, the kidneys or the skin.

In the liver most of the ingested alcohol is oxidised by ADH to AcHO (Acetaldehyde). AcHO itself is oxidised by ALDH(Aldehyde dehydrogenase) to acetate, which is then coupled to coenzyme A and may undergo further oxidation in the Krebs cycle to yield CO2 and H2O or is utilized for the synthesis of fatty acids. All oxidation steps need coenzymes, mainly NAD (Nicotinamide adenine dinucleotide), which is reduced to NADH2(Nicotinamide adenine dinucleotide phosphate).

The resulting shift in the NAD/NADH ratio in part explains the hypoglycaemia, hyperlipidaemia, fatty liver, hyperlactacidaemia and hyperuricaemia that may be the results of alcohol abuse.

Approximately 3-8% of the ingested alcohol are metabolised via the MEOS, in particular the CYP(Cytochrome P 450) 2E1, leading to AcHO as well82. As mentioned earlier, this enzyme-system, in contrary to ADH, may get induced when alcohol is consumed chronically1,82. Since the induction of the MEOS(Microsomal ethanol oxidising system) leads to a faster alcohol oxidation more AcHO is generated which leads to higher blood-AcHO concentrations and therefore more complications due to that toxic substance are expected.

The elimination of alcohol from the body follows zero order kinetics due to saturation of the enzymes involved. On average 0.1-0.2‰/h or roughly 4-10 g/h of alcohol are eliminated in men; women have a slightly lower elimination rate.

Since methionine homeostasis is disturbed in chronic alcoholics as evidenced by higher circulating concentrations of methionine and homocysteine and by the impaired activity of several enzymes involved in the methionine cycle, an impaired ability to supply adequate amounts of cysteine generated from methionine via the transsulfuration pathway for the resynthesis of glutathione may be one explanation for the higher susceptibility of alcoholics.

The elimination of alcohol from the body follows zero order kinetics due to saturation of the enzymes involved. On average 0.1-0.2‰/h or roughly 4-10 g/h of alcohol are eliminated in men; women have a slightly lower elimination rate.