Biomedical subjects
Publications and source records attributed to F Ballet.
Epirubicin is the only anthracycline to be metabolized in humans through a glucuronidation pathway which is not observed in laboratory animals. In search of a model for the experimental study of this metabolism, we have observed that human hepatocytes in culture exhibited this pathway and could be of interest for the understanding of the metabolism of this new drug.
In patients with isolated malignant tumoral hepatomegaly, the investigations performed should aim at excluding a primary carcinoma of the liver and concentrate on the search for primary tumours belonging to 2 main groups: tumours responsive to hormonal treatment or chemotherapy, and obstructive tumours amenable to local palliative measures. In all cases where simple, essentially clinical examinations fail to indicate the cause of the tumoral liver enlargement, further investigations should be based on the histopathological features of the metastases.
The creation of an auxiliary liver by autotransplantation of liver parenchymal cells into the spleen has mainly been studied in rats for the treatment of acute liver failure. In order to apply this procedure to humans with chronic liver insufficiency the aim of this work was: To demonstrate that hepatocytes can survive for long periods after autotransplantation into the spleen; to increase the yield of the isolation of hepatocytes obtained from pig livers since this animal has a more fibrous liver than rats or normal humans and consequently one which is more difficult to dissociate. In 21 pigs isolated hepatocytes were obtained with in collagenase dissociation technique, the yield being 1-3 X 10(7) cells per gram of liver and the viability 70-95%. The hepatocytes survived and maintained normal morphological and histochemical characteristics up to 7 months after transplantation, the date of sacrifice of the last animal.
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Adriamycin (ADR) is used in the treatment of hepatocellular carcinoma (HCC). HCC frequently occurs in association with cirrhosis of the liver. ADR undergoes an extensive hepatic metabolism and biliary secretion. Therefore ADR elimination could be impaired in patients with HCC. In this study we measured the hepatic extraction of ADR by catheterization of the hepatic veins in five patients with HCC associated with cirrhosis or chronic hepatitis. In all patients the hepatic extraction ratio of ADR was very low (less than 0.10) and in four patients it was 10% or less of that of indocyanin green. This suggests that an impairment of ADR hepatic transport exists in these patients.
Twelve patients with unresectable hepatocellular carcinoma associated with cirrhosis were treated with Doxorubicin which was given intravenously (30 to 50 mg/m2) every three weeks. Six patients were given only one dose of Doxorubicin. No clinical response was observed. Five patients has serum alphafoetoprotein (AFP) determination during the treatment. AFP concentration rose in 4 patients and fell in 1 patient. Survival rate after 3 and 8 months of treatment was 58 and 33 per cent. These results suggest that Doxorubicin is not an effective treatment for hepatocellular carcinoma.
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Tumor cells from five human neoplastic effusions were successfully cloned in soft agar and their sensitivity to anticancer drugs was tested. Three patients were resistant in vitro and were found to be resistant in vivo to the same drugs. Two patients were sensitive in vitro and were found to be sensitive in vivo to the same drugs.
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A technique is described for isolation and culture of adult human hepatocytes from surgical liver biopsies. The mean cell yield was 1.75 X 10(7) cells per gm liver and viability averaged 80%. Hepatocytes were maintained in primary culture for about 10 days. Cell morphology and histochemical characteristics were similar to hepatocytes in vivo. Bile canaliculi were observed by electron microscopy. Intracellular albumin was demonstrated up to the 7th day of culture; albumin secretion rate was maximal (0.6 +/- 0.33 micrograms per hr per 10(6) cells) 5 days after plating. These studies demonstrate that adult human hepatocytes can be isolated from surgical biopsies with high yield, and differentiated function can be maintained for several days.
We studied the effects of a series of 16 vasodilators on the intrahepatic vasoconstriction induced by norepinephrine in the isolated perfused rat liver. The vasodilators were nonselective alpha-adrenergic antagonists (phentolamine, ifenprofil, isoxsuprine and buflomedil), a nonselective beta-adrenergic antagonist (propranolol) and an agonist (isoproterenol), an alpha 2-adrenergic agonist (clonidine), calcium channel blockers (verapamil and diltiazem), nitrovasodilators (nitroglycerin, sodium nitroprusside), papaverine and other unclassified vasodilators, some of them with rheological properties (diazoxide, vincamine, cinepazide, naftidofuryl and pentoxifylline). The most potent drugs were ifenprofil, phentolamine, isoxsuprine, clonidine, sodium nitroprusside and buflomedil. Diazoxide, papaverine, pentoxifylline and trinitrine were less powerful. Verapamil, diltiazem, propranolol, isoproterenol, vincamine, cinepazide and naftidofuryl were ineffective. We conclude that different classes of pharmacological agents have significant vasodilatory properties on the hepatic microvasculature. This offers interesting perspectives in the treatment of cirrhosis and stressful states where high levels of circulating norepinephrine may contribute to the altered liver perfusion.
In order to better understand the first steps leading to drug-induced immunoallergic hepatitis, we studied the target of anti-LKM2 autoantibodies appearing in tienilic acid-induced hepatitis, and the target of tienilic acid-reactive metabolites. It was identified as cytochrome P450 2C9, (P450 2C9): indeed, anti-LKM2 specifically recognized P450 2C9, but none of the other P450s tested (including other 2C subfamily members, 2C8 and 2C18). Tienilic acid-reactive metabolite(s) specifically bound to P450 2C9, and experiments with yeast expressing active isolated P450s showed that P450 2C9 was responsible for tienilic acid-reactive metabolite(s) production. Results of qualitative and quantitative covalent binding of tienilic acid metabolite(s) to human liver microsomes were then compared to those obtained with two drugs leading to direct toxic hepatitis, namely, acetaminophen and chloroform. Kinetic constants (Km and Vmax) were measured, and the covalent binding profile of the metabolites to human liver microsomal proteins was studied. Tienilic acid had both the lowest Km and the highest covalent binding rate at pharmacological doses. For acetaminophen and chloroform, several microsomal proteins were covalently bound, while covalent binding was highly specific for tienilic acid and dihydralazine, another drug leading to immunoallergic hepatitis. Although low numbers of drugs were tested, these results led us to think that there may exist a relationship between the specificity of covalent binding and the type of hepatotoxicity.
The effects of norepinephrine (NE) on hepatic amino acid exchanges were studied in the isolated perfused rat liver using a recirculating system with a medium containing amino acids at twice physiologic concentrations. Norepinephrine induced a significant decrease (25%) in portal blood flow at a concentration of 2 ng/ml (10(-8) M). The hormone also increased total hepatic amino acid uptake, essentially through a switch from glutamine release to net uptake. There was no modification in free intracellular amino acids, but glycogen was slightly decreased, and glucose production was increased. Taken as a whole, these results suggest that NE modulates hepatic protein balance.