Zonal location of compensatory hepatocyte proliferation following chemically induced hepatotoxicity in rats and humans.

Hepatocyte proliferation stimulated by partial hepatectomy occurs first in periportal cells, with midlobular and then perivenous cell division occurring later. We have previously shown that this pattern of compensatory cell proliferation also occurs following the hepatotoxicity of N-nitrosodimethylamine. We examined the generality of this pattern in livers of rats given a minimally toxic dose of an hepatotoxin and in liver biopsy samples from patients who had taken overdoses of acetaminophen. Proliferating hepatocytes were detected immunohistochemically (5'-bromodeoxyuridine or Ki-67 antigens). The perivenous necrogens N-nitrosodiethylamine, carbon tetrachloride (CCl4), bromobenzene, and acetaminophen all induced periportal hepatocyte proliferation. With CCl4, bromobenzene, and acetaminophen, the initial appearance of proliferating periportal hepatocytes was followed 12-24 hr later by division in the midlobular region, with a few cells dividing adjacent to the perivenous region of necrosis. The periportal necrogen allyl alcohol also induced periportal cell division. In the human studies, perivenous necrosis was accompanied by periportal and midlobular hepatocyte proliferation. These results suggest that regardless of its lobular location chemically induced hepatotoxicity stimulates cell proliferation that begins in the periportal zone and then moves in an orchestrated response into the midlobular and perivenous zones.