Experimental investigations on alpha‐naphthyl‐iso‐thiocyanate as a hyper‐plastic agent of the biliary ducts in the rat

Abstract

PLATES LXXVI-LXXX) IN previous papers (Mazzanti and Lopez, 1951-52, 1952a and b, 1953a and b ) we have reported that alpha-naphthyl-iso-thiocyanate (A.N.I.) , when introduced either orally or parenterally in different doses, with Werent frequencies, by various modes of application and by different vehicles, exerts a serious toxic action on different species of animals.We have described the alterations that appear in certain organs, particularly in the liver, in the first period of treatment. These consist in hypertrophy of the periportal spaces due to cellular proliferation which spreads and penetrates more or less deeply, through the central zones of the hepatic lobules. I n the present paper we report the results of further investigations on protracted treatment with this drug. Proliferation of small bileducts is evident, with regeneration of reticular fibres and formation of young fibroblasts.On the basis of these observations we re-examined the histological sections from the earlier experiments and noted that the changes begin as a proliferation of apparently undifferentiated cellular elements. Development of solid or hollow tubular structures, considered to be regenerated bileducts, is evident in the liver of rats subjected to this protracted treatment.These observations are of some importance in establishing the fact that a chemical substance, whose nature is well known, has a direct stimulating effect on the growth of the bile-duct epithelium. MATERIALS ANXI XETHODSThe investigations were carried out on 50 male albino rats of the Italic0 strain, weighing, at the beginning of the experiment, between 100 and 150 g. They were given the following standard diet :-whole wheat flour 300 g., whole maize flour 300 g., whole barley flour 300 g., casein 60 g., calcium lactate 30 g., olive oil 20 g. It WBB dissolved in olive oil and added to the diet i n the proportion of 1 g./kg. of mixture. The diet was given ad libitum. Thie dose of A.N.I. allowed the animals to remain in 8 healthy condition. They were killed at intervals ranging from 15 days to 7 months. A.N.I. w&8 obtained from British Drug H o w , Ltd. 243Arch. I&. anat. e h t . pat., xii, 417.

Ribonucleic acid as affected by hepatocarcinogenesis.

“…This non-carcinogenic agent raised the DNA concentration, as was expected in view of the report by Lopez and Mazzanti (1955), now confirmed, that it causes small cells of bile-duct type to proliferate. Although this proliferation must entail some RNA synthesis, it does not call into question the present conclusion that, contrary to the view of Kono (1964), RNA synthesis may be somewhat depressed in the liver as a whole.…”

Isolation, Culture, and Transplantation of Intrahepatic Biliary Epithelial Cells and Oval Cells

“…The first of these types is exemplified by an orderly pro liferation of bile ductular and stromal cells with the resultant formation of well differentiated hyperplastic bile ductules and small ducts. This type of bile ductular hyperplasia is seen in the livers of rats following ligation of the common bile duct [9] or during chronic intoxica tion with a-naphthyl isothiocyanate [10,11] or 4,4'-diaminodiphenylmethane [12]. It has also been termed type I or 'typical' ductular proliferation, and in human liver it is observed in conditions such as extrahepatic biliary obstruction [4], The second type is 'oval cell' pro liferation stimulated during the early stages of hepato carcinogenesis in the liver of rats subjected to treatments with a number of different chemical hepatocarcinogens [13][14][15].…”

Comparison of liver progenitor cells in human atypical ductular reactions with those seen in experimental models of liver injury

“…In humans, typical ductular proliferation is seen in acute extrahepatic biliary obstruction (acute cholestasis), [7][8][9][10][11][12] and is similar to the proliferation of mature, well-formed ducts such as seen after bile duct ligation, ␣-naphtyl-isothiocyante, or 4,4Ј-diaminophenylmethane treatment of rats. [13][14][15][16][17] Atypical ductular reactions occur in chronic cholestatic diseases such as primary biliary cirrhosis, sclerosing cholangitis, or chronic extrahepatic biliary obstruction, in regenerating liver after submassive necrosis, in alcoholic liver disease, 18 in focal nodular hyperplasia, 2,3,[19][20][21] and after liver allograft failure. 22 Atypical ductular reactions consist of bile ductules located adjacent to the parenchyma and arranged in anastomosing cords with poorly defined lumina and small cytoplasmic volume of the lining cells.…”