Effects of the consumption of alcohol in the oral cavity:
Relationship with oral cancer

FIGUERO-RUIZ E, CARRETERO-PELÁEZ MA, CEREZO-LAPIEDRA R, ESPARZA-GÓMEZ G, MORENO-LÓPEZ LA. EFFECTS OF THE CONSUMPTION OF ALCOHOL IN THE ORAL CAVITY: RELATIONSHIP WITH ORAL CANCER. MED ORAL 2004;9:14-23

SUMMARY

In an epidemiologic point of view the consumption of alcoholic beverages is found to be associated to an increased risk for developing an upper gastrointestinal tract cancer. The relation of the studies that establish this connection is complicated due to both the confluence of various risk factors within the same person such as alcohol and tobacco, and to the lack of data that can be verifiable by the clinician. For this reason the exact pathogenic mechanism responsible for this increase of risk is not known since ethanol per se was not confirmed to be carcinogenic. Different hypotheses have been proposed, explaining how ethanol, by oral or systemic route, can act as a risk factor for the development of oral cancer. This article serves as a review of the actual situation of the potential pathogenic mechanisms, dividing them in local and systemic effects. Within the aforementioned special reference is made on the alteration of the oral mucosa permeability, the action of acetaldehyde and the role of retinoids.

Key words: Ethanol, ethyl alcohol, acetaldehyde, alcohol dehydrogenase (ADH), aldehyde dehydrogenase (ALDH), cytochrome P4502E1, retinoids, polymorphisms.

INTRODUCTION

Ethyl alcohol or ethanol, whose chemical formula is CH₃CH₂OH, is the essencial active component of alcoholic beverages (1,2,3). It may be obtained through two elaboration procedures: by fermentation or decomposition of sugars contained in various fruits, and by destillation, consisting of purifying the fermented drink (4).

After the ingestion of an alcoholic drink, the ethanol contained within is absorbed in the small intestines, and in a lesser amount in the large intestines and the stomach, reaching the liver by portal entry, where majority of it is metabolized (5). This metabolism is divided into two stages: the first stage consists of the transformation of ethanol to acetaldehyde, which can be achieved in three ways, by alcohol dehydrogenase (ADH), by hepatic microsomal system (MEOS), and by catalase enzyme. The second stage is characterized by the oxidation of the earlier obtained acetaldehyde into acetate by means of the aldehyde dehydrogenase enzyme (ALDH)(5).

The consumption of alcoholic beverages has repercussions in practically the whole body. Manifesting itself entirely all throughout the bodily organs and systems: nervous (4-6), cardiovascular (5-8), digestive (5-8), sexual (5,6) or at the level of the medula osea (5,6). In the oral cavity it is characterized by the appearance of a series of clinical signs and symptoms triggered by either the direct effect of alcohol in the organism or by the consequence of poor personal hygiene. In this manner, significant indices of caries (6,9), calculus (6,9), sialosis (10-15), bruxism (6,9), leukoplakia (16-22) and erythroplasia (23-25) are found in chronic alcoholics. With regards to lichen planus, ethanol could be implicated in its potential transformation process to malignancy (26-29).

ALCOHOL AND ORAL CANCER

From an epidemiologic viewpoint, chronic consumption of alcoholic beverages is associated with an increased risk for the upper gastrointestinal tract cancer (30-43). Establishing a direct cause-effect relation between both entities turns out to be difficult. This is due to the frequent association of alcohol with other risk bearing practices such as cigarrette smoking, as well as the lack of objective data that can serve the clinician, which have been based on the information given by the patient when it comes to the quantity ingested.

Although multiple explanations exist in trying to explain the promoting effect of alcohol, the pathogenic mechanism is not clear (30). The reason for which is because ethanol as such has not been verified to be carcinogenic (30,44). Thus various hypotheses have been proposed in the explanation for ethanol acting as a risk factor, locally or systemically, in the development of oral cancer.

LOCAL EFFECT:

The local process is the most studied, since the mouth is the external part of the body that is in contact with alcohol. In this moment the components that form part of the beverages are encountered in their maximum concentration which later on undergo various transformation processes mediated by the enzymatic systems of the body.

-1. Increase in permeability

The alcohol in contact with the oral mucosa is capable of producing an alteration in morphology characterized by an epithelial atrophy (14,34,38,45), which means an increase in the susceptibility of the said tissue against other carcinogenic chemicals. In this manner, it was suggested that ethanol is capable of increasing the penetration of carcinogens through the oral mucosa (16,38,46), due to both their increase in solubility (16,38), and an increase in the permeability of the oral mucosa (5,38,47,48). The said increase is explained by the dissolvent effect of ethanol, capable of eliminating the lipid component of the barrier present in the oral cavity formed by the derived lipids of the membrane that surround the granules of the epithelial spinous layer (37). However, for other authors as Trigkas (49) or Howie (47), the increase in permeability would be due to the reorganization of the elements constituting the cell membrane, as observed in samples of lingual tissues of recent human cadavers, wherein ethanol is capable of increasing the penetration of molecules of high molecular weight without producing any type of variation in its lipid component.

-2. Action of Acetaldehyde:

The increase in the oral mucosa permeability is not enough to explain the major risk for developing oral cancer in alcoholic drinkers. This has determined the search for other mechanisms associated to the consumption of ethanol.

Since ethanol by itself has not been proven to be carcinogenic (44), the role of its first metabolite, acetaldehyde, has been postulated as a potential factor implicated in the effects of the consumption of alcoholic drinks. The International Agency for Research on Cancer (IARC) has established that sufficient evidence exists to identify acetaldehyde as carcinogenic in animals, being possibly carcinogenic to humans (50,51). Various studies have been focused in identifying the effects of acetaldehyde. In short term cellular cultures it causes mutations and other damages to the DNA; in vitro they form compounds with the DNA and in vivo they initiate the transformation of rat kidney cells and inhibit the repair of DNA. It appears to be a nasal tract carcinogen when inhaled by rodents in a laboratory; It interferes with the synthesis and reparation of DNA, and consecuently the development of tumors; It induces interchanges in sister cromatids; produces specific gene mutations; inhibits the O6methylguanitransferase, enzyme responsible for repairing the injury caused by alkylating agents; It unites to cellular proteins and DNA provoking morphologic and cellular injury; Its components are neoantigens that determine the production of antibodies, stimulating the immune system and inducing a cytotoxic immune response and it is also capable of in vitro follic acid destruction (30,34,52-54).

Thus, due to the important role that acetaldehyde seems to play in the development of oral cancer, it is considered that all those situations in which its accumulation is determined, either due to an increase in its production or to a decrease in its elimination, supposes a major risk.

Oral Metabolism of Acetaldehyde:

As what happens in the liver, the metabolism of etanol in the oral cavity is characterized by a primary oxidation, which transforms it into acetaldehyde by means of the DNA present in both the oral microflora and the cells of the oral mucosa. In the same way as by means of the cytochrome P4502E1 brought about by ethanol. Later the acetaldehyde will suffer a second oxidation through ALDH, which transforms it into acetate, hampering the toxic activity of the first metabolite (5).

Therefore the accumulation of acetaldehyde can be due to an increase in the activity of ADH in the oral microflora, the ADH of the cells of the oral mucosa and the cytochrome P4502E1 or a decrease in the activity of the ADLH.

2.1 Role of ADH in the oral microflora

The role of the oral microflora in the oxidation of ethanol has been studied by Homann (30-33) who demonstrated the production of considerable quantities of acetaldehyde during the social consumption of alcohol. This author has demonstrated that subjects with tendency to the aerobic flora (Streptococcus salivarius, Streptococcus viridans hemolytic var., Corynebacterium sp., Stomatococcus sp., fungi) present a major production of salivary acetaldehyde. In such a way that the ethanol seems to increase the bacterial production of acetaldehyde in a dose-dependent manner, and from quantities superior to 40 grams of ethanol a day (30,34).

In this same line of investigation Homann (33) has found an relation between the low levels of oral hygiene present in alcoholic subjects and a bacterial overgrowth, which reflects in a significant concentration of salivary acetaldehyde in this route. This explains the increase of risk for oral cancer in alcoholic patients with poor oral health (34, 55).

The acetlaldehyde dissolved in the saliva is distributed throughout the upper gastrointestinal tract (30) acting on the covering mucosa. Upon which direct exertion of its effects is facilitated, either by means of an increase in its permeability, permitting the passage of other carcinogens or by penetrating in the epithelial cells and causing injury on the DNA. To this respect, it is possible to point out the study by Homann in 1997 (31) where the effect of acetaldehyde on the oral mucosa of a group of rats in an eight-month period was analyzed by means of biopsies. No type of dysplastic, neither microscopic nor macroscopic cancerous lesion was found; major indices of epithelial proliferation were observed in the experimental group of rats. Nevertheless, this state of hyperproliferation might constitute the first step in the genesis of oral cancer due to the cells in continuous state of replication presenting the possibility of accumulating major errors that might give rise to the appearance of mutations, and even due to the fact that the cells in this phase are more susceptible to the action of other carcinogens that might cross its membrane and generate irreversible injury (30).

2.2 Role of ADH of the oral mucosa.

Thanks to its small molecular size, ethanol is capable of passing through cellular membranes through simple diffusion (5) and allows the ADH activity of the oral epithelial cells to transform it into acetaldehyde, which will be accumulated intracellularly, exerting its effects on the epithelial DNA (37,38). ADH has been described to be found in the cells of the oral mucosa presenting a high affinity constant (Km). Which implies that in a small amount it will contribute to the metabolism of ethanol (the greater the value of the affinity constant, the lesser is the affinity of ADH for ethanol and therefore lesser transformation to acetaldehyde). (30). The human ADH complex is found localized in the long arm of chromosome 4, with five genes, ADH₁, ADH₂, ADH₃, ADH₄, ADH₅. ADH₃ is polymorphous in caucasians (Arg ²⁷¹Gln and Ile³⁴⁹Val) for which ADH₃¹ (Arg²⁷¹ and ile³⁴⁹) and ADH₃² are spoken of (56). According to the studies done by Bosron in 1986 (57), those enzymes that are coded by the allele ADH₃¹ metabolize ethanol to acetaldehyde two to three times faster than those that codify their enzymes from the allele ADH₃². This will imply a major accumulation of acetaldehyde, giving rise to the hypothesis that the homozygotic subjects for the allele ADH₃^1-1 present a major risk for cancer induced by alcohol. In 1997, Harty (52) in Puerto Rico and Coutelle (58) in France, found that those subjects with the genotype ADH₃¹₁ present a greater risk for oral cancer than ADH₃²₂. In other more recent studies as those of Bouchardy 2000 (59), Olshan 2001 (60), Schwartz, 2001 (56) no increased risk is found for oropharyngeal cancer in drinkers with ADH₃¹₁ genotype. This lack of correlation is explained when valuing the importance of the ADH₃ in the metabolism of ethanol, it is observed that this is not the main metabolic means (60). In the same way, it is also impotant to take into account that the differences in the genetic risks for alleles of ADH₃ are only rendered important for chronic exposures to elevated quantities of ethanol (60).

2.3. Cytochrome P450.

Cytochrome P4502E1 is found in the smooth endoplasmic reticulum and participates in the oxidation of ethanol when ethanol levels are superior to 50-80 mg/dl (5). Two genetic polymorphisms are known for this cytochrome: Rsa/Pst I, with two alleles: c1 and c2; and the Dral polymorphisms, with alleles D y C (59). Various studies suggest that the variant allele c2 and c are associated with an increase in enzymatic activity of cytochrome P4502E1 (48, 61), that implies a significant accumulation of acetaldehyde within the epithelial cells of the oral cavity, increasing the risk for the development of oral cancer.

On the other hand, the cytochrome P4502E1 is capable of increasing the development of oral cancer in an indirect manner, by means of activating procarcinogens and increasing the production of radical toxins (34). These effects have mostly been studied in relation to colon cancer. However, future researches that approach this knowledge to the oral cavity field are necessary.

2.4 ALDH Activity

The second means through which acetaldehyde can accumulate at oral cavity level, is like consequence to a decrease in its elimination. For acetaldehyde to be transformed to acetate the action of aldehyde dehydrogenase enzyme, most responsible for its metabolism, is necessary (5, 50). In this manner, any alteration at the level of this enzyme would suppose an increase in the accumulation of acetaldehyde.

Just as what would occur with the alcohol dehydrogenase enzyme, the alterations in the enzymatic activity of the ALDH is found associated to its different isoforms. ALDH is a tetrameric protein located within the mitochondrias, of which two isoenzymes are known: ALDHI and ALDHII (34,50). The ALDHII is coded by the locus ALDH 2 of chromosome 12. It has been observed that 40% of american indians and 50% of orientals have a modified isoenzyme of different activity (change of lysine to glutamine in the remaining 487). Subjects with the allele ALDH II2 codify inactive enzymes, by having low affinity to acetaldehyde, which makes them incapable to metabolize it, presenting high levels of intracellular acetaldehyde. Both Yokohama 1996 (54), and Väkeväinen, 2000 (62) find a major risk for oral cancer in subjects with inactive forms of ALDH II.

-3. Alteration in retinoid metabolism.

Although the role of acetaldehyde in the development of oral cancer seems to be quite clear, a new route of investigation has been proposed with the role of retinoids in the development of precancerous lesions. Chronic consumption of ethanol is found associated with decreased levels of retinoids in the oral cavity (34).

Vitamin A and its synthetic derivatives constitute the retinoids, small molecules involved in different biological functions such as growth regulation and wide variety of cellular differentiation (34, 63,64); for which any alteration in metabolism and activation will reflect in an increase in the oral mucosa susceptibility to other carcinogens (63). In experimental animals a relation between vitamin A deficiency and a high incidence of cancer has been found, so as an increase in the susceptibility of chemical carcinogens (63).

In order for the retinoids to exert their functions an enzymatic conversion of retinol (vitamin A) to an active binding protein (retinoic acid) that will be capable of uniting itself to the receptors of retinoic acid localized in the nucleus of the cell, controlling the gene expressions that mediates its effects (65). Ethanol is a competetive inhibitor of retinol metabolism, since the same enzyme (ADH) is in charge of catalyzing two reactions in which an accumulation of retinol will be produced, in the expense of the reduction of retinoic acid, making this the active form (34, 56). At the same time, the first metabolite of ethanol, acetaldehyde, is also capable of inhibiting the generation of retinoic acid (64). On the other hand, ethanol apparently causes a deficiency of retinoic acid in the liver due to an increase in its catabolism mediated by the action of cytochrome P4502E1 induced by ethanol (64).

The low levels of retinoic acid suppose a lack of control in epithelial growth, which could initiate the development of malignant lesions. Presently retinoids are being employed in the treatment of cancerous and precancerous lesions with partial and total remissions of leucoplakia demonstrated in 40-60% of the patients in systemic vitamin A treatment, though their topical use seem to have a limited effect (63).

SYSTEMIC EFFECT

Different theories have been proposed trying to explain the relation between the consumption of alcoholic drinks and the development of oral cancer, due to the effect that ethanol exerts on organs distant to the oral cavity. The most important are those made on the liver, since it deals with the principal center of product metabolism. Not only will it not be capable of being used as a source of energy, but also will constitute potential carcinogens. Among them, ethanol itself, which due to the lack of transformation will stay longer in the blood, acting as a possible carcinogen.

-1. At hepatic level

The increase of ethanol levels in the liver supposes that all liver functions will be centered in its metabolic transformation, which in turn will originate an alteration in the metabolism of the rest of the substances. This determines that the detoxification of certain compounds (37, 46, 66) and the activation (66) of others, with potential carcinogenic activity, will be impeded.

The taking up of the nutrients is also altered, due to the metabolic processes being occupied in the transformation of ethanol and its correct metabolism being hampered (67). As we add this to the subject's carefree attitude in having a healthy and equilibrated diet (6), and the high tendency to vomiting (5), we find ourselves with subjects with high nutritional deficiencies. Some of which are directly associated with a major prevalence to oral cancer (67), and in other cases, entail a state of generalized bodily weakness, which will present a major risk for any pathology (37, 66). The depression of the immune system associated to the chronic consumption of ethanol contributes the aggravation of this situation.

-2. At salivary gland level

Lastly, the effect of ethanol at salivary gland level is pointed out. These are seen altered from a morphologic and functional point of view, through the degeneration of its autonomic innervation, by way of its own fatty infiltration, with a painless, symmetric and bilateral size increase of the parotid glands, and a decrease in salivary flow. Leading to the accumulation of carcinogens on the surface of the oral mucosa and increasing the risk for oral cancer (11, 14, 37, 38, 68-72).

However, it is difficult to establish a direct relationship between the systemic alterations associated to the consumption of alcoholic drinks and the development of cancer in a local form at the level of the oral cavity. Thus, and since the epidemiological evidence demonstrate the existence of association, it would be interesting to accomplish future studies focused on this systemic role.

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