[Light and electron microscopic studies on the dose and time dependency of the hepatotoxicity of benzopyrones]

Both male and female Wistar rats were treated with daily oral doses of a combination of the active components coumarin and troxerutin (Venalot-Depot) corresponding to 1, 8, 64 and 128 mg coumarin/kg b.w., respectively. Goal of the study was to study coumarin at the target organ liver for a longer period, after it had turned out from a fertility and teratogenicity study that liver alterations were observed in the P-generation following the elevated doses' treatment up to 10 weeks (male) and 3 weeks (female). Light and electron microscopic examinations of the livers revealed the following findings: The lesions are dose- and time-dependent. First signs of coumarin-induced hepatocellular alterations are fine granular protein-like precipitations in the region of the sER (smooth endoplasmatic reticulum) which conflux to large areas. The glycogen content decreases significantly at the same time. This is followed by an osmotically controlled water redistribution in the cytoplasm and an increased water inflow from the extracellular space (vacuolar degeneration) as well as an overload of the cytoplasm with lipids, taken in by nutrition. Doses of 64 and 128 mg/kg b.w. of the test substance produced extensive hepatic alterations, associated with hypertrophy of the liver, with a focal onset in the globular periphery, subsequently extending to peripheral and intermediate lobular areas. Since light or electron microscopic alterations were not observed following doses of 1 and 8 mg/kg b.w., the dose of 8 mg coumarin/kg b.w. can be determined as no effect dose for the rat.(ABSTRACT TRUNCATED AT 250 WORDS)