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Biomedical subjects

D S Sarma

Publications and source records attributed to D S Sarma.

At least 91 records · Page 5Linked to original sources
PubMed1983

Distinctive biochemical pattern associated with resistance of hepatocytes in hepatocyte nodules during liver carcinogenesis.

Hepatocyte ("hyperplastic") nodules induced in the liver by initiation with diethylnitrosamine and selected by dietary 2-acetylaminofluorene plus partial hepatectomy ("resistant hepatocyte model") have a special pattern of biochemical behavior and metabolic activity different than that seen acutely with many xenobiotics including many promoting agents and carcinogens. The nodule cells show a very low uptake of 2-acetylaminofluorene, relative to surrounding and normal liver, low levels of activity in the cytochromes P-450 and aryl hydrocarbon hydroxylase, high levels of activity in gamma-glutamyltransferase, microsomal epoxide hydrolase, soluble glutathione-S-transferase and soluble UDP-glucuronyltransferase (UDP-GT(1)) and elevated levels of glutathione. This metabolic pattern appears to maximize the resistance of the nodules to xenobiotics generally, such as 2-acetylaminofluorene, and thereby may account for the resistant behavior of nodule hepatocytes to the inhibition of cell proliferation and the cytotoxicity by 2-acetylaminofluorene and other carcinogens. The possible importance of this seemingly new metabolic program in carcinogenesis is discussed briefly.

2-Acetylaminofluorene↗
PubMed1983

Resistance to hepatotoxins acquired by hepatocytes during liver regeneration.

The appearance of resistance to a number of hepatotoxins in primary cultures of hepatocytes prepared at various time intervals up to 2 weeks after partial hepatectomy is the major focus in this study. Resistance to the cytocidal effect of aflatoxin B1, 2-acetylaminofluorene, N-hydroxy-2-acetylaminofluorene, methotrexate, or methyl methanesulfonate shows a progressive increase until 48 hr and then returns to the resting level of susceptibility by 2 weeks. The genesis of mutagens from 2-acetylaminofluorene and aflatoxin B1 by S-9 liver fractions shows a decrease from and return to control values after partial hepatectomy that parallels the resistance. The levels of total cellular cytochromes P-450 also decrease following partial hepatectomy and remain from 28 to 36% less than those of controls for at least 1 week. The glutathione and total soluble sulfhydryl ("glutathione") content increase following partial hepatectomy, and the pattern is consistent with a partial role for glutathione in the resistance phenomenon as it relates to 2-acetylaminofluorene. The possible relationship between resistance to the cytocidal effects in vitro and the resistance to inhibition of cell proliferation in vivo during liver carcinogenesis is discussed.

2-Acetylaminofluorene↗
PubMed1982

Effects of delays in the cell cycle on the induction of preneoplastic and neoplastic lesions in rat liver by 1,2-dimethylhydrazine.

This study was designed to explore further the relationship between cell proliferation and the induction of early putative preneoplastic lesions by carcinogens. Rats were given a non-necrogenic dose of 1,2-dimethylhydrazine 24 hr before being subjected to partial hepatectomy. Beginning 4 hr later, hydrocortisone was injected 10 times at 4-hr intervals to delay progression through the cell cycle, including inhibition of DNA synthesis by at least 85% for about 40 hr. At the appropriate time thereafter, the putative preneoplastic hepatocytes were selectively stimulated to grow in vivo into gamma-glutamyltransferase-positive focal lesions. Animals given hydrocortisone showed a large decrease (71%) in the number of gamma-glutamyltransferase-positive foci. In contrast, when hydrocortisone was given at 6 days after partial hepatectomy, no inhibition in the induction of hepatic lesions was observed. In the next experiments, rats were treated with 1,2-dimethylhydrazine and were subjected to partial hepatectomy at 12, 24, or 48 hr or 1 week thereafter. A significant number of gamma-glutamyltransferase-positive foci was found when partial hepatectomy was performed at 12 or 24 hr but far fewer were found when the operative partial hepatectomy was delayed to 48 hr or 1 week later. Similarly, in long-term experiments, six of 14 animals developed primary hepatocellular carcinoma 13 months after the time of injection of 1,2-dimethylhydrazine when partial hepatectomy was performed at 12 hr, while none of the animals developed liver cancer when the operation was performed at 48 hr. These results imply that the majority of biochemical lesions induced by 1,2-dimethylhydrazine that are relevant to the induction of liver preneoplasia and neoplasia are short-lived and that their persistence is associated with some cellular activity closely related to the cell cycle.

Animals↗
PubMed1981

Requirement of cell proliferation for the initiation of liver carcinogenesis as assayed by three different procedures.

Experiments were designed to determine the role of cell proliferation in the initiation of liver carcinogenesis induced by chemicals. To investigate this, two methylating carcinogens, N-methyl-N-nitrosourea and 1,2-dimethylhydrazine, were used as the initiating carcinogens. The initiated hepatocytes were monitored by selectively stimulating them to grow into focal islands of presumptive preneoplastic hepatocytes. The experimental approach in brief consisted of the following. Rats received a nonnecrogenic dose of the carcinogen; at a time period when the carcinogen could no longer be detected in the system, they were subjected to either partial or sham hepatectomy. The initiated cell thus formed were selectively stimulated to grow into foci of preneoplastic hepatocytes using three different selection regimens: (a) feeding a diet containing 0.02% 2-acetylaminofluorene plus one administration of carbon tetrachloride (2 ml/kg body weight) intragastrically; (b) feeding a diet containing 0.05% phenobarbital; and (c) feeding a choline-deficient diet. The foci were quantitated by staining them for the presence of gamma-glutamyltransferase. The results obtained indicate that irrespective of the type of selection procedure used foci of preneoplastic hepatocytes were seen only in rats that received the carcinogen coupled with a cell-proliferative stimulus such as partial hepatectomy. Very few or no foci were seen in rats that received the carcinogen plus sham hepatectomy. These results suggest that cell proliferation plays an important role in the initiation of liver carcinogenesis by chemicals.

Animals↗
PubMed1981

Role of acute hepatic necrosis in the induction of early steps in liver carcinogenesis by diethylnitrosamine.

Experiments were performed to assess the role of liver cell necrosis in the induction of early steps in liver carcinogenesis with diethylnitrosamine, as measured by the appearance of foci of resistant hepatocytes that stain for gamma-glutamyl transpeptidase and that are presumptive preneoplastic lesions in the rat. With the use of a necrogenic dose of diethylnitrosamine and an assay for the carcinogen-induced early stages or resistant hepatocytes, the number of enzyme-altered foci was decreased to a major extent (up to 62%) by posttreatment with diethyldithiocarbamate, a derivative of disulfiram. Such posttreatment decreased to a large degree (78%) the cumulative labeling index of hepatocytes following an initial exposure to diethylnitrosamine. The performance of partial hepatectomy up to 68 hr after such posttreatment restored the level of induction of the resistant hepatocytes. Nonnecrogenic doses of diethylnitrosamine or dimethylnitrosamine induced virtually no foci of resistant hepatocytes but did so when coupled with cell proliferation. These results establish clearly an important role for liver cell necrosis in the production of early steps in liver carcinogenesis in one model. The mechanism for this effect appears to be by the induction of compensatory liver cell proliferation.

Animals↗
PubMed1980

In vivo replication of hepatic deoxyribonucleic acid of rats treated with dimethylnitrosamine: presence of dimethylnitrosamine-induced O6-methylguanine, N7-methylguanine, and N3-methyladenine in the replicated hybrid deoxyribonucleic acid.

Experiments were designed to determine whether some chemical lesions such as O6-methylguanine, N7-methylguanine, and N3-methyladenine induced in rat liver DNA by the hepatocarcinogen dimethylnitrosamine permit replication in vivo. For this purpose, [14C]dimethylnitrosamine was administered to methylate the parental strand of liver DNA. Four hours later, a time period when the carcinogen cannot be detected in either the liver or the blood, rats were subjected to partial hepatectomy in order to induce DNA replication. During the S phase, 5-bromo-2-deoxyuridine was administered to render the newly made strands heavy. The rebanded, hybrid, hepatic DNA of density 1.714 g/cm3 and greater was pooled from the neutral cesium chloride gradient, dialyzed, and lyophilized. The hybrid DNA was then treated with S1 nuclease to digest any single-stranded regions. The results obtained indicated the presence of O6-methylguanine, N7-methylguanine, and N3-methyladenine in S1 nuclease resistant, hybrid DNA. The results are interpreted to indicate that these chemical lesions permitted in vivo DNA replication.

Adenine↗
PubMed1980

Carcinogen-DNA interaction: differential effects of distamycin-a and spermine on the formation of 7-methylguanine in DNA by N-methyl-N-nitrosourea, methylmethanesulfonate, and dimethylsulfate.

Experiments were designed to determine whether DNA conformation and sequence play any role in its methylation by N-methyl-N-nitrosourea, methylmethanesulfonate, and dimethylsulfate, agents that are known to methylate DNA by different mechanisms but yield 7-methylguanine as the major product. The approach taken was to bind ligands to DNA that interact with it stereospecifically and to study their effect on the formation of 7-methylguanine by the three methylating agents. The results indicate that both distamycin A and spermine shielded the formation of 7-methylguanine in vitro in rat liver DNA by N-methyl-N-nitrosourea but not by methylmethanesulfonate or dimethylsulfate; they did not, however, protect 2-deoxyguanylic acid against methylation by N-methyl-N-nitrosourea. Based on the mechanism by which the methylating agents and the ligands react with DNA, these results are interpreted to suggest that 1) guanines methylatable at the N-7 position by N-methyl-N-nitrosourea are located at, or close to, the binding sites of the ligands, probably the A-T-rich regions, and those methylatable by methylmethanesulfonate and dimethylsulfate are distal to these regions, and/or 2) the conformation DNA assumes in the presence of distamycin A or spermine permits methylation by methylmethanesulfonate and dimethylsulfate but not by N-methyl-N-nitrosourea. The study implicates DNA structure and/or its sequences in carcinogen-DNA interaction.

Animals↗
PubMed1980

The sequential analysis of liver cell necrosis: inhibition of diethylnitrosamine- and dimethylnitrosamine-induced acute liver cell death by posttreatment with diethyldithiocarbamate.

Posttreatment with diethyldithiocarbamate (DEDTC) largely prevented the development of acute hepatocellular necrosis induced by diethylnitrosamine (DEN) and dimethylnitrosamine (DMN) in male Fischer rats as monitored by the release of glutamate-pyruvate transaminase and sorbitol dehydrogenase into the serum and by histologic examination. Liver cell necrosis was evident with a dose of 25 mg of DEN/kg and was progressive with increasing doses of DEN. DEDTC (50 mg/kg; three times at 4-hour intervals) was given at 4 or 8 hours after the administration of DEN (100 mg/kg), time points at which at least 50% and 75%, respectively, of the administered DEN had disappeared from both the serum and liver. Under these conditions, DEDTC prevented liver cell necrosis, except for a few isolated cells. Similar inhibition was also observed when DEDTC was given 4 hours after the administration of a necrogenic dose of DMN (20 mg/kg). DEDTC, when administered 4 hours after DEN, delayed the rate of clearance of DEN and of ethylation of DNA and RNA but did not significantly affect the total extent of ethylation of rat liver nucleic acids. These results offer further support for the multistep hypothesis for the development of liver cell necrosis.

Animals↗
PubMed1980

Persistence of resistant putative preneoplastic hepatocytes induced by N-nitrosodiethylamine or N-methyl-N-nitrosourea.

The administration of either N-nitrosodiethylamine (diethyl-nitrosamine) to intact male F-344 rats or N-methyl-N-nitrosourea to similar animals 18 hr after partial hepatectomy results in the induction of altered resistant hepatocytes that persist for up to 36 weeks with no perceptible decrease in their number. The criterion for resistance was the ability to proliferate rapidly and to develop into foci or nodules when exposed to a level of dietary 2-acetylaminofluorene that inhibits the proliferation of the vast majority of hepatocytes when liver cell proliferation is stimulated by surgical or chemical partial hepatectomy. Since this selection procedure, when coupled with a single dose of diethylnitrosamine, is associated with a high incidence of liver cancer as compared to appropriate controls, and since similar foci and nodules were shown previously to be one site of origin for hepatocellular carcinoma in this model, the induction of resistant hepatocytes is interpreted as initiation. Thus, these results suggest that initiation of liver carcinogenesis in this model is irreversible, at least for a period of 36 weeks.

2-Acetylaminofluorene↗
PubMed1979

Induction of hepatic neoplastic lesions in mice with a single dose of hycanthone methanesulfonate after partial hepatectomy.

Experiments were designed to determine whether hycanthone methanesulfonate (1-([2-(diethylamino)ethyl]amino)-4-(hydroxymethyl)thioxanthen-9-one monomethanesulfonate), an antischistosomal drug, and its analog, IA-4-N-oxide (8-chloro-2-[2-(diethylamino)ethyl]-2H-[1]benzothiopyrano[4,3,2-cd]indazole 5-methanol monomethanesulfonate), will induce neoplastic lesions in the livers of mice not infected with Schistosoma mansoni. All the mice received a single i.m. injection of hycanthone methanesulfonate (76 mg/kg), IA-4-N-oxide (80 mg/kg), or an equivalent volume of the solvent, 0.9% NaCl solution, 42 hr after partial hepatectomy. Of the mice receiving hycanthone methanesulfonate and living 200 days or longer, hepatocellular carcinoma was seen in 11.5% and liver sarcoma was seen in 4.2%. This type of malignant neoplasm was not seen in the animals receiving either IA-4-N-oxide or 0.9% NaCl solution. In addition, mice receiving hycanthone methanesulfonate showed a significantly higher incidence of both type 1 (43% compared to 21% in controls) and type 2 (21% compared to 12% in controls) hepatocyte neoplasms. Mice receiving IA-4-N-oxide showed no increased incidence of neoplasms.

Animals↗