ZONAL LOCATION OF COMPENSATORY HEPATOCYTE PROLIFERATION FOLLOWING CHEMICALLY-INDUCED HEPATOTOXICITY IN RATS AND HUMANS

Hepatocyte proliferation stimulated by partial hepatectomy occurs firs t in periportal cells, with midlobular and then perivenous cell divisi on occurring later. We have previously shown that this pattern of comp ensatory cell proliferation also occurs following the hepatotoxicity o f N-nitrosodimethylamine. We examined the generality of this pattern i n livers of rats given a minimally toxic dose of an hepatotoxin and in liver biopsy samples from patients who had taken overdoses of acetami nophen. Proliferating hepatocytes were detected immunohistochemically (5'-bromodeoxyuridine or Ki-67 antigens). The perivenous necrogens N-n itrosodiethylamine, carbon tetrachloride (CCl4), bromobenzene, and ace taminophen all induced periportal hepatocyte proliferation. With CCl4, bromobenzene, and acetaminophen, the initial appearance of proliferat ing periportal hepatocytes was followed 12-24 hr later by division in the midlobular region, with a few cells dividing adjacent to the periv enous region of necrosis. The periportal necrogen allyl alcohol also i nduced periportal cell division. In the human studies, perivenous necr osis was accompanied by periportal and midlobular hepatocyte prolifera tion. These results suggest that regardless of its lobular location ch emically induced hepatotoxicity stimulates cell proliferation that beg ins in the periportal zone and then moves in an orchestrated response into the midlobular and perivenous zones.