Introduction: Evolution of Intragastric Ethanol Infusion Model

PAPERS published in this meeting report constitute the proceedings of a workshop held in the annual Research Society on Alcoholism meeting in San Antonio, June 24, 1993. This workshop, entitled "Rat Intragastric Ethanol Infusion Model: Current Progress in Studies on Alcobol-Induced Organ Injury," represented the second gathering of investigators who have u ~ this model in their respective interest of research. It was also attended by scientists who had practical or intellectual interest in the model, as well as several distinguished investigators in the field of alcohol research. The workshop was indeed a stimulating, fruitful, and rewarding experience and undoubtedly served as a place not only to exchange research findings, modifications, and different applications of the model, but also to help clarify and standardize several versions of the model developed during the past years. The latter is a critical concept for the model to continue to be used by more investigators in a reproducible manner. Currently, seven laboratories in the United States, one in Sweden, and one in Japan employ the model for investigations on a variety of subjects ranging from ethanol metabolism to alcohol-induced liver, kidney, pancreas, and heart injury. In addition, many laboratories in the US and Europe are studying tissues from this model. From these laboratories, seven papers were presented at the workshop, and two additional contributions have been made to this proceedings. The proceedings were divided into two major components based upon the common themes: 1) roles of oxidant stress and eicosanoids in experimental alcoholic liver disease and 2) ethanol-induced extrahepatic organ injury. We would like to introduce each of these intriguing papers as we review the evolution that this model has experienced for the past 10 years. For those who have attempted to use rodents as animal models of alcohol-induced organ injury, it usually is an unescapable recognition that some methods other than voluntary consumption of ethanol-containing water or liquid diet have to be devised to achieve sufficient ethanol intake and reproduction of the wider spectrum of alcohol-induced organ pathology. Ten years ago, a long-term rat ethanol intragastric infusion model was developed solely for this purpose (13,18). Rationales for development of such a model were 1) to overcome rats' natural aversion to ethanol and achieve sufficient ethanol intake; 2) to keep up with the rats' high rate of ethanol metabolism, which is attributable to their high basal metabolic rate; 3) to have absolute control over the amount and the pattern of nutrient and ethanol intake; and 4) to facilitate easy dietary manipulation and parallel pair-feeding without variability. In fact, the use of this model enabled the studies, which would be impossible otherwise. Using the model, we successfully rendered for the first time to rats progressively increasing doses of ethanol intake well beyond 36% calories (14), a level which had been considered to be a maximum with other models. This initial experiment has led to three important novel observations. First, we came to recognize that the rat has a capacity of developing a remarkable tolerance to ethanol, certainly much more than what had been considered until then. Blood alcohol levels (BALs) ranging up to 350 mge/e are well tolerated by these chronically and continuously intoxicated animals without any obvious physical signs of intoxication. Above 350 mg%, slight ataxia on the hind limbs develops, and systemic inhibitory effects on motor activities or reflexes do not ensue until BALs reache 500-600 mg%. Thus, the reported BAL of 150-200 mg% in other models may actually represent a light level of ethanol intoxication. Secondly, daffy determination of BALs in these animals revealed previously unreported cyclical patterns independent of whether constant or variable dose was infused (16). This cyclic and oscillative phenomenon exhibited an average threshold BAL of 207 mg%, above which an increase in elimination rate occurred. Dr. Badger discusses in his paper the possible molecular basis for this phenomenon involving transcriptional activation of cytochrome P4502E1 (CYP2E1). If this mechanism indeed underfies the cyclical BAL, this molecular explanation may also have a significant implication for pathogenesis of alcoholic liver disease (ALD), since the degree of induction of the secondary system responsible for the cyclical phenomenon was shown to correlate well with progression of ALD (15). The third observation we made with the use of this model was the confirmation of a hypothesis originally put