The goal of these studies is: first, to define mechanisms regulating carcinogen metabolism in the intact liver and in sublobular zones of the liver lobule, and second, to evaluate the role of the liver in exporting products of benzo(a)pyrene metabolism to extrahepatic tissues. This latter goal will be approached by studying the release of benzo(a)pyrene conjugates and phenols from livers preloaded with benzo(a)pyrene and transplanted into normal rats. Monooxygenation and conjugation reactions involving benzo(a)pyrene and ethoxycoumarin in periportal and pericentral regions of the intact liver lobule will be studied employing unique miniature fiber-optics and O2electrodes in the perfused liver. These data will be compared with ultramicrobiochemical analyses of biochemical intermediates in microdissected samples of sublobular zones from lyophilized sections of liver. Acute effects of selected substrates (e.g., fatty acids, bile salts and cholesterol) and hormones (e.g., epinephrine, glucagon) on carcinogen and drug metabolism in perfused livers, isolated hepatocytes and periportal and pericentral zones of the liver will be determined. These studies will provide new insights into the role of sublobular structure, microcirculation and bile production present in the intact liver but absent in hepatocytes on regulation of drug and carcinogen metabolism. It is essential that we understand the very important interactions which occur between diet and cancer. Thus, another aim of this work is to examine the effects of a chronic high fat or calorie-restricted diet on benzo(a)pyrene and 7-ethoxycoumarin metabolism in liver. The former diet increases and the latter decreases the frequency of tumors in laboratory animals. A new initiative will also be undertaken to develop methods to study influences of chronic dietary manipulation on the uptake, storage and export of benzo(a)pyrene conjugates to target tissues in vivo. Important knowledge acquired from these studies will lead to deeper insights into links between intermediary and carcinogen metabolism which may be applied ultimately to the prevention of cancer in man through rational nutritional means.
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