Search PubMed⌕ Search

Biomedical subjects

E Farber

Publications and source records attributed to E Farber.

At least 37 records · Page 2Linked to original sources
PubMed1994

Altered expression of cytochrome P450 mRNA during chemical-induced hepatocarcinogenesis and following partial hepatectomy.

Levels of various cytochrome P450 proteins have been reported to be decreased to varying degrees in chemically induced hepatocyte nodules and following partial hepatectomy (PH). By screening a rat liver lambda ZAP cDNA expression library with antibodies raised against a partially purified preparation of cytochrome P450 isolated from untreated male Fischer 344 rats, we have isolated a 1.1-kb cDNA. This cDNA was sequenced for 139 bases from the 5' end of the sense strand and comparison of the resulting sequence with the sequences in Gene Man DNA data bank revealed 95% homology of the sequenced portion with male-specific rat cytochrome P450 (M-1, CYP IIC11). The 32P-labeled cDNA was used as a hybridization probe on RNA blots (Northern blots) prepared with total RNA from rat livers obtained post PH, from aflatoxin B1(AFB1)-induced rat liver tumors and from rat liver nodules induced with a combination of diethylnitrosamine/acetylaminofluorene/PH (DEN/AFF/PH). At 36 and 72 hr post PH, the mRNA level was decreased by > 93%. Relative to the corresponding control livers, the mRNA level was also decreased by 97% in the liver nodules and by 57% in AFB1-induced liver tumors. The RNA blots derived from the liver nodules and AFB1-induced liver tumors were also probed with a cDNA probe (R17) that recognizes other cytochromes P450 (CYP IIB1/CYP IIB2). The mRNA corresponding to CYP IIB1/CYP IIB2 was also depressed 92% in the nodules and 65% in the tumors. These results clearly indicate that the depression of both CYP IIC11 and IIB1/IIB2 in the hepatic nodules and the tumors is related to the inhibition of transcription and/or enhanced degradation of the mRNA.

Animals↗
PubMed1994

Programmed cell death: necrosis versus apoptosis.

Cell death remains poorly understood, despite its obvious importance in every organ and tissue in a wide variety of biological processes, including, of course, the many pathological. The past few years have seen an amazing expansion of interest in cell death in normal development and maturation, in the pathogenesis of many acute and chronic diseases, and in the therapy of some diseases, especially malignant neoplastic diseases and some hyperplastic diseases such as psoriasis. This expansion has included an unusual interest in a supposedly new form of cell death, a "programmed cell death," designated "apoptosis." This is proposed as a hitherto undescribed form of cell death in contrast to the classical cell death, necrosis. Apoptosis is considered by some, especially by nonpathologists, to represent quite a different type of cell death. A review of the literature on on apoptosis, programmed cell death, necrosis, etc. indicates that there is no field of basic cell biology and cell pathology that is more confusing and more unintelligible than the area of apoptosis versus necrosis. If any degree of clarity is to develop in our understanding of the fundamental principles underlying cell death of any type, it is incumbent upon us to rethink "from square one" the scientific analysis of how cells die and how can we assess cell death in a reasonably rational manner.

Animals↗
PubMed1993

Small encapsulated hepatocellular carcinoma of the liver. Provisional analysis of pathogenetic mechanisms.

BACKGROUND: Small hepatocellular carcinomas frequently were found incidentally during routine pathologic examinations of adult livers removed at liver transplant. METHODS: Sixty-nine carcinomas of all sizes were found in 25 patients; 39 of the tumors were smaller than 1 cm in diameter, and 18 of the carcinomas in five patients were not clinically suspected. These small incidental carcinomas lend themselves to analysis of the morphologic basis of human hepatocellular carcinogenesis. RESULTS: All of these tumors arose in cirrhotic livers. Most of the small carcinomas were multilobulated and subdivided by pre-existing fibrous septa. The surrounding capsule usually was not a true capsule. They were all well differentiated, most formed bile, Mallory bodies, or showed alpha-1-antitrypsin (A1AT) positivity. Transition from cirrhotic nodular parenchyma to areas of hyperplasia or atypical hyperplasia to well-differentiated carcinoma were common. Large cell dysplasia also was common. CONCLUSIONS: These morphologic transitions closely parallel changes seen in experimental chemical carcinogenesis. They also strongly suggest a multicentric origin of the tumors. In addition, in every instance, the lesions were multiple in the liver and involved both lobes. This latter finding has possible implications for recurrence after local surgical excision of small hepatocellular carcinomas.

Adult↗
PubMed1993

Sequential alterations in tRNA population of 2-acetylaminofluorene-induced hepatocyte nodules.

In order to investigate the possible mechanisms by which cellular alterations can start an altered onco-developmental gene expression, we studied tRNA distribution profiles during the early steps of 2-acetylaminofluorene-induced hepatocarcinogenesis. The finding of progressive and sequential alterations appears to support the hypothesis of a causal connection between tRNA changes and nodular cell proliferation, possibly through the disruption of the mechanism which regulates tRNA functional adaptation.

2-Acetylaminofluorene↗
PubMed1993

Is carcinogenesis fundamentally adversarial-confrontational or physiologic-adaptive?

The dominant dogma concerning the essential cellular changes during preneoplasia and precancer considers these as abnormal or foreign that evoke a basic "host-parasite" response. An alternative view of how cancer develops, here briefly outlined, views the early and intermediate cellular changes as essentially physiologic and adaptive. This different concept introduces clonal adaptation as a basic response to many genotoxic carcinogenic stimuli including chemicals, radiations, and some viruses. The evidence in support of this new view of the carcinogenic process is summarized.

Animals↗
PubMed1993

Choline deficiency, lipotrope deficiency and the development of liver disease including liver cancer: a new perspective.

Thus, the pathologic consequences of feeding a CD diet are fatty liver, liver cell death, liver cell proliferation, and liver cell cancer. The fatty liver with CD is similar to that with other types of fatty liver in that the most attractive current hypothesis is based on some interference with the production and output of VLDL by the liver. The induction of cell death appears to be consistent with quite a different hypothesis, genesis and/or increase in liver free radicals leading to both acute necrosis and initiation of carcinogenesis. Especially noteworthy is the low incidence of liver cirrhosis, even after 2 years of exposure to the CD diet. The feeding of the CD diet reproducibly induces severe and persistent fatty liver coupled with extensive cell death, a combination that is frequently considered to be appropriate for the induction of "micronodular" (fatty) cirrhosis in humans. The findings with the LD diet, the high incidence of cirrhosis, with severe persistent fatty liver without significant cell death, together with the low incidence of cirrhosis with the CD diet, stand out as unpredictable and strange, according to current concepts of the pathogenesis of human cirrhosis. The CD model offers an unusual opportunity to explore in increasing detail the possible roles of free radicals in two important problems in pathology and medicine-acute cell injury and neoplasia. The challenges include mechanistic studies on how the free radicals are generated and how they relate to the biological consequences. The relatively slow sequential changes in the induction of cell injury and neoplasia makes the CD model one of the best for mechanistic studies relating to free radicals.

Carcinoma, Hepatocellular↗
PubMed1992

Effect of MNU on the methylation pattern of hepatic DNA during compensatory cell proliferation.

We have used the initiation-promotion model of MNU-induced hepatocarcinogenesis to test the hypothesis that alteration of the methylation status of DNA cytosines could be involved in the initiation of carcinogenesis. In fact cell proliferation plays a fundamental role in the initiation of liver carcinogenesis and hepatocytes in the S phase are more sensitive towards MNU initiation than at other times in the cycle. The molecular mechanisms involved in these processes, however, are still poorly understood and it seemed of value to monitor the DNA methylation status in this system. The results obtained indicate that MNU hepatocarcinogenic action might consist also of the inhibition of DNA hypomethylation biologically associated with cell proliferation.

Animals↗
PubMed1992

Changes in fatty acid composition of phospholipids from liver microsomes and nuclei in rats fed a choline-free diet.

Male F-344 rats were fed a choline-free (CF) diet, and changes in phospholipid content, phospholipid fatty acids and phospholipase A2 activity in liver nuclei and microsomes were examined during the first 72 hr. Both nuclei and microsomes showed a decrease in phosphatidylcholine (PC) content. Microsomes showed an increase in PC arachidonate while nuclei showed a decrease. Also, microsomes showed increased activity of phospholipase A2 (PLA2) while nuclei did not. These observations are consistent with the hypothesis that the absence of diene conjugates in liver microsomes in the rats on the CF diet may reflect the increased rate of removal of peroxidized fatty acids by phospholipase A2.

Animals↗
PubMed1992

The cancer-initiating potential of the fumonisin B mycotoxins.

The cancer-initiating potential of the fumonisin B (FB) mycotoxins produced by Fusarium moniliforme was screened in rat liver for their ability to induce rare hepatocytes with an acquired resistance to the mitoinhibitory effect of 2-acetyl-aminofluorene (2-AAF). Two different initiating protocols were used: a feeding regimen during which FB1 was fed at a dietary level of 0.1% for 26 days, and another where single or multiple doses of FB1 and FB2 (varying from 200 to 50 mg/kg) were administered (by gavage) to hepatectomized rats. In both cases promotion was effected by a 2-acetylamino-fluorene/carbontetrachloride treatment. Cancer initiation was only obtained after the prolonged feeding regimen, indicating that the fumonisins are poor cancer initiators. FB1 and FB2 also lack genotoxic effects in the in vivo and in vitro DNA repair assays in primary hepatocytes. Although FB1 primarily affects the liver, it is not very cytotoxic to primary hepatocytes when compared to aflatoxin B1.

2-Acetylaminofluorene↗
PubMed1991

Counteracting effects of dexamethasone and alpha 2-macroglobulin on inhibition of proliferation of normal and neoplastic rat hepatocytes by transforming growth factors-beta type 1 and type 2.

Primary cultures of hepatocytes isolated from normal F-344 rats or from F-344 rats with hepatocellular carcinomas generated by a 2-step model of chemical carcinogenesis were used to determine if dexamethasone (DEX) or alpha 2-macroglobulin (alpha 2M) modify the ability of transforming growth factors-beta type I (TGF-beta I) and type 2 (TGF-beta 2) to inhibit labelling index of hepatocytes cultured continuously with or without epidermal growth factor (EGF). Both TGF-beta 1 and beta 2 were equivalently potent inhibitors of S-phase DNA synthesis in normal and neoplastic hepatocytes as determined by 3H-thymidine autoradiography. Both DEX (1 to 100 microM) and alpha 2M (50-200 microM) partially counteracted the mito-inhibitory effect of both TGF-betas on the proliferation of normal and surrounding hepatocytes. In contrast, neoplastic hepatocytes cultured with DEX released much less immunoreactive alpha 2M and were less able to overcome the inhibitory effect of TGF-beta than normal or surrounding hepatocytes. Purified bovine alpha 2M partially counteracted the inhibition of TGF-beta 1 or beta 2 of both surrounding and neoplastic hepatocytes. Both DEX and alpha 2M were more effective against the mito-inhibitory activity of TGF-beta 2. Our data suggest that alpha 2M released by DEX-treated normal hepatocytes contributes to the counteraction of the TGF-beta effect by DEX. Our results support the hypothesis that glucocorticoids and growth-factor-binding proteins may have important roles in modulating the effects of TGF-beta on normal hepatocyte proliferation and suggest that under some conditions hepatocellular neoplasms can be more sensitive than normal hepatocytes to inhibition of proliferation by TGF-beta.

Animals↗
PubMed1991

Hepatocyte proliferation in stepwise development of experimental liver cell cancer.

Cell proliferation is the most central and key phenotypic property of cancer including hepatocellular carcinoma. Hepatocyte proliferation is central not only at the late steps in carcinogenesis, the cancer, but at the earliest known step, initiation. Compensatory or regenerative hepatocyte proliferation is essential to initiation with chemical carcinogens but primary hyperplasia is ineffective. During promotion, hepatocyte proliferation is the major change seen as clonal proliferation to generate nodules occurs. During progression, autonomous hepatocyte proliferation balanced by cell loss makes its appearance. This continues in a balanced fashion with only a slight excess of proliferation over loss until the earlier steps in malignancy at which time the balance is disrupted.

Animals↗
PubMed1991

Transitory DNA hypomethylation during liver cell proliferation induced by a single dose of lead nitrate.

In the present study we have examined the effect of a single dose of the mitogen lead nitrate (75 mumols/kg body wt) on the methylation status of hepatic DNA in male Wistar rats. It was found that extensive hypomethylation of hepatic DNA occurs in mitogen-treated rat liver. This effect could be seen as early as 12 h after metal treatment and parallels the changes in liver weight. Probing with the methylation-sensitive enzymes HpaII, MspI, and HaeIII confirmed HPLC analyses and showed that methylation at these sites was affected by lead treatment. DNA hypomethylation has already been found in regenerating rat liver and in hepatic (pre)malignant lesions when compared to normal nondividing liver. Thus the lowering of the DNA 5-methylcytosine content appears to be a property characteristic of cellular proliferation, regardless of whether it is caused by partial hepatectomy, carcinogen treatments, or mitogen administration.

Animals↗
PubMed1990

Protective activity of different hepatic cytosolic glutathione S-transferases against DNA-binding metabolites of aflatoxin B1.

To evaluate the role of glutathione S-transferase (GST) isoenzymes in induced resistance of hepatocytes to aflatoxin B1 (AFB1), we compared DNA protective activities of different hepatic cytosol preparations and purified GSTs from normal rats, rats exposed to different polychlorinated biphenyls (PCBs), and rats with carcinogen-induced hepatocellular neoplasms, with cytosols or purified GSTs from mouse, rainbow trout, and human livers. These comparisons were performed in an in vitro assay for [3H]AFB1-DNA binding after activation by rat liver microsomes. Cytosol and S-hexylglutathione-affinity-purified GST preparations from livers of mice consistently had strong protective activity against AFB1-DNA binding. The majority of this activity was dependent on the presence of reduced glutathione (GSH) but some GSH-independent protection was observed in mouse hepatic cytosol, but not in purified GST preparations. We found that all of the GSH-dependent DNA-protective activity in mouse liver eluted as a single GST isoenzyme by hydroxyapatite chromatography. Preparations of cytosol and purified GSTs from normal rat liver, rainbow trout liver, and human liver had much less AFB1-specific DNA protective activity than GSTs found in mouse liver preparations. Cytosol from rats with carcinogen-generated liver neoplasms and livers induced with 3,3',4,4'-tetrachlorobiphenyl and 2,2',4,4',5,5'-hexachlorobiphenyl had more GST activity toward CDNB than cytosol from normal rat liver. When equivalent units of GST activity (CDNB) were compared, there was little difference observed between the DNA-protective activities of PCB-induced and normal rat liver cytosols, yet cytosol from rat liver neoplasms was more protective. Purified GST-P (7-7), the GST isoenzyme most induced in carcinogen-generated rat liver neoplasms, was not protective when added at protein concentrations found to be protective for total GSTs isolated from these neoplasms. These studies demonstrate that the resistance of mouse liver to AFB1 can be explained primarily by a single constitutive GST isoenzyme (YaYa or 4-4) with a relatively high activity toward DNA-binding metabolites of AFB1. GST isoenzymes with such high specific DNA protective activity against AFB1 metabolites were not evident in human, rat, or rainbow trout liver or in PCB-induced or neoplastic rat liver preparations.

Aflatoxin B1↗