Intracellular proteolytic systems in alcohol-induced tissue injury

Alcohol Research & Health, Winter, 2003 by Terrence M. Donohue, Jr., Natalia A. Osna

The calpains are believed to be involved in several physiological processes, including the maturation and processing of certain enzymes and the breakdown of proteins associated with the cytoskeleton--a complex array of proteins that gives cells their shapes and enables them to contract and divide. Because calpains are responsible for the proteolysis of cytoskeletal proteins, investigators have suggested that calpain activity is involved in modulating cell structure in both normal and pathological states. For example, the calpains may have a major role in nerve cell development. Under pathological conditions, however, the same enzymes can become "over-activated," resulting in extensive degradation of structural proteins and subsequent cell damage (Johnson and Guttmann 1997).

Effects of Alcohol Consumption on the Calpains. Studies of how alcohol consumption affects the calpains have largely been restricted to the brain. Like the liver, the brain is significantly affected by excessive alcohol consumption, which ultimately can result in alcohol-related nerve cell degeneration. Recent studies examining the effects of alcohol consumption on calpain activity in the brain demonstrated that the activity of these enzymes is elevated in the brains of alcohol-fed animals compared with untreated animals (Rajgopal and Vemuri 2002). Furthermore, the brains of alcohol-fed animals had higher levels of the degradation products of a cytoskeletal protein called spectrin, which is degraded by calpains. Researchers believe that the activation of calpain in this instance results from an alcohol-induced increase in calcium concentrations within the nerve cells (Rajgopal and Vemuri 2002). Thus, in contrast to the lysosomal and ubiquitin-proteasome systems, which are inhibited by chronic alcohol consumption, the activity of the calpain system is enhanced by chronic alcohol consumption. Excessive or untimely protein degradation, however, can be just as harmful to the organism as reduced protein degradation.

CONCLUSIONS

This article has described the effects of alcohol consumption on the functions of three major proteolytic pathways that regulate the quantity and the types of proteins inside cells. Through a variety of mechanisms, alcohol significantly influences each of these proteolytic pathways, interfering with their normal functions. All of these changes, however, can lead to the same end results: cell death and tissue injury, which may contribute to liver disease and other physiological damage associated with chronic alcohol consumption. Although researchers have learned much about alcohol and its effects on proteolytic systems, just as many issues remain to be explored. For example, the identity of the molecules that inhibit lysosome assembly and cause proteasome inhibition has not yet been determined. The apparent paradox that NF[kappa]B activation and the resulting inflammation occur during proteasome inhibition also requires further elaboration. Finally, researchers should investigate whether these proteolytic systems can be employed as therapeutic targets. For example, the proteasome, which is inhibited by a large number of agents, also can be activated by several small molecules, including some naturally occurring lipids (Dahlmann et al. 1993). Consequently, the administration of these compounds to alcohol-treated animals or cells may conceivably reactivate partially inactivated proteasomes and thus restore normal protein degradation after alcohol exposure.