The use of the Tsukamoto-French rat model of alcoholic liver disease facilitated pathological, physiological, biochemical and cell biological experiments that examined the validity of some of the existing hypotheses for pathogenesis of alcoholic liver necrosis and fibrosis. Results obtained to date strongly support the contribution of centrilobular hypoxia as a pathogenetic mechanism of alcoholic liver necrosis. The enhanced hepatic lipid peroxidation was not evident at the early stage of ethanol-induced liver necrosis but could be demonstrated at the late stage when the liver damage progressed to liver fibrosis. This suggests that the lipid peroxidation may not be an important mechanism of alcoholic liver necrosis but may be an initiation factor for liver fibrogenesis as recently proposed by others (88). The high-fat diet appears to have promoting effects on both induction of alcoholic liver necrosis and stimulation of liver fibrogenesis. The former may be related to the induction of MEOS by the high-fat diet and consequent centrilobular hypoxia caused by inadequately compensated hepatic overuse of oxygen. The latter can be mediated through sensitization of Ito cells by a high-fat diet. We propose that Kupffer cell-derived TGF beta is, at least in part, responsible for some of phenotypical changes of Ito cells associated with their activation. Our model provides maximal experimental control and induces the discrete stages of alcoholic liver injury that can be reproduced with its pathological evolution telescoped into a short time. Because of these features, replication of the experimental conditions in different laboratories is possible so that results can be validly compared through precise standardization of the experimental protocols. This model requires some training in implantation and maintenance of the gastric catheter. However, the training can be easily attained by anyone who has experience in animal surgery. Another requirement is the initial fund to acquire infusion devices and metabolism cages. Once this equipment is purchased, however, the maintenance cost is low. Even if the initial expenses are included, the cost per animal is relatively inexpensive when compared with the cost involved in the use of larger animals such as baboons or pigs. Since administration of diet and ethanol (or isocaloric glucose solution) is precisely controlled by infusion pumps, this system makes unnecessary the measurement of diet consumption that has to be done daily for each animal with other methods.(ABSTRACT TRUNCATED AT 250 WORDS)