VIII - Digestive System 2

Abstract

Most diagnostic work with human liver biopsies is based on light microscopy and paraffin-embedded tissue sections, with correlation of clinical data and blood chemistry findings. The same is true of hepatic tissue in preclinical toxicity studies. However, transmission and scanning electron microscopy as well as a wide variety of other techniques including cytochemistry, immunocytochemistry, and more recently the polymerase chain reaction and in situ hybridization are helpful in the understanding of both human hepatic disease and hepatic changes observed with novel pharmaceutical agents in preclinical safety studies. The liver represents the principle organ of biotransformation, and hepatic oxidation is a major drug metabolizing process carried out by the cytochrome P450 monooxygenase system. P450 cytochromes play an important role in hepatic metabolism of drugs in man and are the most often assessed by many pharmaceutical companies with human in vitro microsome preparations in support of the development of new drug candidates However, the study of the metabolism of drugs is complicated by the fact that their metabolism in vivo is seldom through one single enzymatic pathway. Moreover, there are significant species differences in the responses of the cytochrome P450 dependant monooxygenasesystem to drugs whether inducers and inhibitors. It has also been suggested that age-related changes in hepatic drug metabolism are partly due to age-related changes in ploidy status of hepatocytes.