In order to reveal the precursor lesion of hepatocellular carcinoma, a histopathologic study was performed on 141 cases of liver cirrhosis with or without hepatocellular carcinoma. Exclusive of primary or metastatic hepatocellular carcinoma nodules, 94 nodular lesions (greater than 5 mm) were detected in 53 cirrhotic livers. They consisted of 83 large regenerative nodules and 11 dysplastic nodules. Besides some common features with those observed in the former type, the dysplastic nodules presented increased cytoplasmic basophilia, nuclear and nucleolar enlargement, nuclear crowding, occasional microacinar formation and proliferation of the hepatocytes within fibrous septa. These changes were not substantial enough to allow the diagnosis of hepatocellular carcinoma. In one case, however, malignant transformation of hepatocytes was suspected because of their pattern of extranodular outgrowth. It is important to recognize these subtle abnormalities in order to define premalignant hepatic lesions. A possible connection between benign large regenerative nodules and dysplastic nodules is also discussed.

Carcinoma, Hepatocellular↗

PubMedDate not supplied

Intratracheal administration of microcystin-LR, and its distribution.

Microcystin-LR (MCLR) was injected into mice intratracheally, absorption from the lungs was easy and it was confirmed that both the cause of death and lethality dose level were the same as by intraperitoneal injection treatment. An immunostaining method revealed that there was a time lag of about 60 min before accumulation of MCLR, and that it caused bleeding in the liver. Clearance from internal organs took about 2 weeks; during the initial stage (the first 2 days), the small intestine, kidney, cecum and large intestine were already involved. However, even after 2 weeks, small amounts of MCLR were still present in epithelial cells in the gastrointestinal mucosa.

Absorption↗

PubMedDate not supplied

Formation, characterization, and toxicity of the glutathione and cysteine conjugates of toxic heptapeptide microcystins.

Microcystins LR, YR, and RR, cyclic heptapeptide hepatotoxins produced by cyanobacteria, were synthetically converted into glutathione (GSH) and cysteine (Cys) conjugates. Fast atom bombardment mass spectra showed [M + H]+ ions corresponding to GSH and Cys conjugates of microcystins LR, YR, and RR for the obtained compounds. 1H NMR spectral analyses revealed that two singlet signals of olefinic protons of N-methyldehydroalanine (Mdha) in microcystins disappeared in the conjugates, confirming that thiols of GSH and Cys added nucleophilically to the alpha, beta-unsaturated carbonyl of the Mdha moiety. On examination of the 50% lethal dose (LD50) with intravenous injection using mice, both GSH and Cys conjugates showed reduction in toxicity compared with microcystins, but their toxicity still remained. Microcystin LR and its GSH conjugate were separated and identified in a standard mixture by using a frit-fast atom bombardment liquid chromatography/mass spectrometry (Frit-FAB LC/MS) method. Obtained conjugates in the present study would be important compounds as the standard samples for study of metabolism of microcystins, and the Frit-FAB LC/MS method would be applicable to mass spectrometric identification of metabolites of microcystins.

Animals↗