Search PubMed⌕ Search

Biomedical subjects

E Farber

Publications and source records attributed to E Farber.

At least 91 records · Page 5Linked to original sources
PubMed1986

The pattern of metabolism of 2-acetylaminofluorene in carcinogen-induced hepatocyte nodules in comparison to normal liver.

This study was designed to test further the hypothesis that the special biochemical pattern seen in hepatocyte nodules during liver carcinogenesis could be of fundamental importance in their selective metabolism of one carcinogenic xenobiotic, 2-AAF, as related to their resistance to xenobiotics. Nodules of a certain stage were induced using the resistant hepatocyte model. The metabolism of a single small dose of 2-AAF in hepatocyte nodules in comparison to normal liver was studied at different time intervals up to 30 h. The levels of free 2-AAF in nodules and in normal liver were approximately the same over the whole time period. However, the nodules showed a large decrease in the binding of 2-AAF to DNA, RNA and proteins as well as in the metabolic conversion to hydroxylated forms, both free and conjugated with glucuronic acid. The patterns of metabolic conversion to metabolites and of conjugation of the metabolites are in harmony with the known biochemical patterns in nodules, a decrease in phase I components involved in the metabolism of carcinogens and other xenobiotics and an increase in most phase II components involved in conjugation and detoxification.

2-Acetylaminofluorene↗
PubMed1986

Influences of different polychlorinated biphenyls on cytocidal, mitoinhibitory, and nodule-selecting activities of N-2-fluorenylacetamide in rat liver.

The influences of different polychlorinated biphenyl (PCB) isomers and congeners on distinct hepatotoxic responses to the hepatocarcinogen N-2-fluorenylacetamide [(2-FAA) CAS: 53-96-3] were examined in F344 rats. Cytocidal toxicity of 2-FAA (25-400 microM), determined by lactate dehydrogenase release during 20 hours in primary monolayer cultures of isolated rat hepatocytes, was reduced by in vivo pretreatment with either phenobarbitone [(PB) CAS: 50-06-6] or 2,2',4,4',5,5'-hexachlorobiphenyl (HCBP), a PB-type PCB inducer. However, cytocidal toxicity of 2-FAA was substantially potentiated by either 3-methylcholanthrene [(MCA) CAS: 56-49-5] or 3,3',4,4'-tetrachlorobiphenyl [(TCBP) CAS: 32598-13-3], an MCA-type PCB. In the same cell culture assays, all four pretreatments similarly reduced cytocidal toxicity of N-hydroxy-N-2-fluorenylacetamide (0.32-32 microM; CAS: 53-95-2). By comparison, pretreatments with either the PB-type or MCA-type PCB's (50-200 mumol/kg) diminished mitoinhibitory toxicity of 2-FAA in vivo, as measured by hepatic regenerative growth and hepatocyte labeling indices 7 days after partial hepatectomy (PH) in rats given 3 consecutive daily doses of 2-FAA (20/mg/kg/day) before PH. This regimen of 2-FAA and PH promoted rapid selective growth of gamma-glutamyltranspeptidase-positive (gamma-GT+) nodules at 2 and 4 weeks after PH in rats previously given an initiating hepatocarcinogen, diethylnitrosamine [(DENA) CAS: 55-18-5]. However, various PCB's, including 2,2',4,4',5,5'-HCBP, 3,3',4,4'-TCBP, 2,2',4,4'-TCBP, 2,2',5,5'-TCBP, and the commercial mixture Aroclor 1254, each given as a single dose of 50 mumol/kg by gavage 10 days after DENA and 7 days before 2-FAA, all reduced the size of 2-FAA-selected gamma-GT+ nodules during the 4-week period after PH. These results indicate that, in spite of predictable inducer-specific opposite influences of different types of PCB's on cytocidal toxicity of 2-FAA, all PCB's similarly reduce nodule selection by 2-FAA in initiated livers. Reduced growth of 2-FAA-selected nodules correlated with the consistent ability of all PCB's to enhance regeneration of liver mass after 2-FAA and PH.

2-Acetylaminofluorene↗
PubMed1986

Allogeneic hepatocyte transplantation in the rat spleen under cyclosporine immunosuppression.

An innovative approach for stimulating the rapid growth of allogeneic hepatocytes implanted into splenic tissue with maintenance of the structural integrity is described. Single cell suspensions of hepatocytes from normal male ACI-strain rats (RTIa) were injected (2 X 10(6) cells) into the spleen of allogeneic male Fischer (RTI1) recipient rats. A 70% partial hepatectomy (PH) was performed at the same time as hepatocyte transplantation. Animals were treated for 4 days prior to, and 1 day after, transplantation with a feeding regimen containing 0.05% 2-acetylaminofluorene (AAF) to inhibit regeneration of the residual host liver. Animals received cyclosporine (CsA) 3 mg/kg/day s.c. posttransplantation. Histological examination of a standard longitudinal section of the recipient spleen two days posttransplant revealed an approximately 0.54-mm2 area replaced by hepatocytes. By 7 days this had increased to 0.97 +/- .15 mm2. Without CsA administration, hepatocytes were undetected at 7 days. Both PH and AAF treatment were necessary for successful colonization and sustained proliferation. Withdrawal of CsA treatment at 10 days after transplantation resulted in rapid rejection of established hepatocytes. This study demonstrates that rapid colonization of the rat spleen with allogeneic hepatocytes can be achieved, and that the viability and structural integrity of these transplanted cells can be maintained for at least 14 days using cyclosporine immunosuppression.

2-Acetylaminofluorene↗
PubMed1986

Some emerging general principles in the pathogenesis of hepatocellular carcinoma.

A rational concept of the key steps in the multistep process of cancer development in liver is emerging. This concept proposes that the strategy of cancer development consists of two major sequences: (a) the genesis of persistent benign focal proliferations (clonal nodules) and (b) the development of hepatocellular cancer from one or more such nodules. Sequence (a) comprises the classical 'initiation and promotion' of chemical carcinogenesis. Sequence (b) is dominated by persistent cell proliferation. In the precancerous steps, cell proliferation is almost balanced by cell loss, leading to only a slow increase in the size of the nodules. With cancer, this balance is lost, leading to a much more rapid enlargement of the focal lesion. The carcinogenic process in the liver is viewed initially as a form of physiological adaptation to certain types of xenobiotic agents generating new focal cell populations. The animals with such new focal lesions are much better able to resist the toxic or lethal effects of many environmental hazards. According to this view, liver cancer development is a consequence of a derivative of the basic adaptation process.

Adaptation, Physiological↗
PubMed1986

Sequential alterations in growth control and cell dynamics of rat hepatocytes in early precancerous steps in hepatocarcinogenesis.

This set of experiments is the second of a series designed to explore alterations in cell dynamics and growth control of new populations of hepatocytes that appear to play a role in the carcinogenic process induced in the liver by chemical carcinogens. This is part of an ongoing study of the biochemical and molecular basis for cancer development. A rat model for hepatocarcinogenesis, the resistant hepatocyte model, was chosen with its synchrony of several steps in the process. Carcinogenesis was initiated by the administration of a single necrogenic dose of diethylnitrosamine. Resistant hepatocytes so induced were stimulated to proliferate rapidly to form nodules by a mitogenic stimulus in the presence of a brief exposure to dietary 2-acetylaminofluorene sufficient to inhibit the proliferation of the majority of uninitiated hepatocytes, the nonresistant population. A small subset of these hepatocyte nodules, the persistent nodules, was examined at 2, 4, and 6 mo postinitiation. Duration of phases of the cell cycle, growth fraction, doubling time, cell death, and cell loss and the responses and subsequent recovery after the application of a strong mitogenic stimulus, partial hepatectomy, were measured. The first precancerous hepatocyte nodule, at 2 mo, showed a "normal" duration of phases of the cell cycle. The growth fractions were about 4,4, and 8% at 2, 4, and 6 mo, respectively, as compared to 0.4% in the surrounding hepatocytes. Accompanying the increased growth fractions were considerable levels of cell loss, measuring about 3% at 2 mo and 7% at 6 mo. At 6 mo, the hepatocyte nodule population, unlike the hepatocytes in the surrounding liver, shows a failure to return to its base-line level after stimulation of cell proliferation by partial hepatectomy. The results of this study have identified two new steps in the early precancerous phase of hepatocarcinogenesis relating to alterations in the control of cell proliferation and are consistent with the hypothesis that new and evolving cell populations may play an important role in the step-by-step carcinogenic process. These new populations appear to acquire alterations in growth control in a seriatim fashion, with retention of some "normal" properties.

Animals↗
PubMed1985

1,2-Dibromoethane initiation of hepatic nodules in Sprague-Dawley rats selected with Solt-Farber system.

Initiating effects of the fumigant 1,2-dibromoethane (DBE) for liver were examined using the Solt-Farber selection system. Male Sprague Dawley rats (230-260 g) were given one oral dose of DBE (75 mg/kg), a two-thirds partial hepatectomy 4 h later, five oral doses of 2-acetylamidofluorene (AAF) (25 mg/kg) on days 17-21, CCl4 (2 ml/kg) on day 22, a booster dose of AAF (10 mg/kg) on day 32, and were sacrificed on day 82. Nodules and appreciable gamma-glutamyl transpeptidase foci were found in the livers of four of six animals given DBE, but not in any animals of the control group.

2-Acetylaminofluorene↗
PubMed1985

Tamoxifen alone or in combination with estradiol-17 beta inhibits the growth and malignant transformation of hepatic hyperplastic nodules.

Hepatic hyperplastic nodules (HHNs) induced by the 'resistant hepatocyte method' of Solt et al. were studied as an experimental prototype of oral contraceptive-related tumors. Cytoplasmic estrogen receptors were present in all HHNs harvested and their concentration was always less than that in normal liver. No specific cytoplasmic progestin receptors could be measured in the above tumor or liver specimens. The long-term administration of estradiol-17 beta (4.8-24.0 micrograms/day) resulted in the death of all but one of 20 animals prior to termination at 10 months. Tamoxifen (0.25-2.5 mg biweekly), which did not lead to excess mortality, decreased HHN grade (proportion of liver slice occupied by HHN) and inhibited malignant transformation. Combination therapy with single-dose estradiol-17 beta (4.8 micrograms/day) and various doses of tamoxifen (0.25-2.5 mg biweekly) in most cases reduced mortality, HHN grade and malignant transformation. Cytoplasmic progestin receptors were absent and estrogen receptors were either undetectable or present in low concentrations in hepatic tumors harvested at the time of termination. Our results indicated that HHNs are hormone-dependent and that malignant transformation can be inhibited by tamoxifen alone or in combination with estradiol-17 beta.

Animals↗
PubMed1985

Tamoxifen alone or in combination with estradiol-17 beta inhibits the growth and malignant transformation of hepatic hyperplastic nodules.

Hepatic hyperplastic nodules (HHNs) induced by the 'resistant hepatocyte method' of Solt and Farber were studied as an experimental prototype of oral contraceptive-related tumors. Cytoplasmic estrogen receptors were present in all HHNs harvested and their concentration was always less than that in normal liver. No specific cytoplasmic progestin receptors could be measured in the above tumor or liver specimens. The long-term administration of estradiol-17 beta (4.8-24.0 micrograms/day) resulted in the death of all but one of 20 animals prior to termination at 10 months. Tamoxifen (0.25-2.5 mg biweekly) which did not lead to excess mortality, decreased HHN grade (proportion of liver slice occupied by HHN) and inhibited malignant transformation. Combination therapy with single-dose estradiol-17 beta (4.8 micrograms/day) and various doses of tamoxifen (0.25-2.5 mg biweekly) in most cases reduced mortality, HHN grade and malignant transformation. Cytoplasmic progestin receptors were absent and estrogen receptors were either undetectable or present in low concentration in hepatic tumors harvested at the time of termination. Our results indicate that HHNs are hormone-dependent and that malignant transformation can be inhibited by tamoxifen alone or in combination with estradiol-17 beta.

Animals↗
PubMed1985

A common biochemical pattern in preneoplastic hepatocyte nodules generated in four different models in the rat.

Hepatocyte nodules, structures consistently seen in every model of liver carcinogenesis well before the first appearance of cancer, were examined with respect to some Phase I and Phase II components considered to be important in the metabolism of carcinogens and other xenobiotics. Phase I components are those related to the metabolism of xenobiotics and include microsomal cytochromes P-450 and mixed-function oxygenase activities. Phase II components are those related to the conjugation and detoxification reactions of xenobiotics and their metabolites and include glutathione S-transferases and glutathione. Nodules were induced by the resistant hepatocyte, choline-deficient, methionine-low diet, phenobarbital and orotic acid models of liver carcinogenesis. Also, nodules generated by the resistant hepatocyte model were examined after transplantation to the spleen of syngeneic animals. The hepatocyte nodules show a common biochemical pattern, consisting of decreased microsomal cytochromes P-450, cytochrome b5, and aminopyrine N-demethylase activity and increased glutathione and gamma-glutamyltransferase in whole homogenates and glutathione S-transferase activity in the cytosol. This similarity, appropriate to a resistance phenotype, adds additional support for the hypothesis that hepatocyte nodules may be a common step in liver carcinogenesis in several different models.

Aminopyrine N-Demethylase↗
PubMed1985

Intestinal metaplasia as a common option of oval cells in relation to cholangiofibrosis in liver of rats exposed to 2-acetylaminofluorene.

Oval cell proliferation in the liver was studied in rats exposed to dietary 2-acetylaminofluorene for 2 weeks with partial hepatectomy performed midway at 1 week. Using autoradiography after either continuous or pulse exposure to [3H]thymidine, histochemical staining for leucine aminopeptidase and gamma-glutamyltransferase, and transmission electron microscopy, we found that every animal showed islands of oval cells with small intestinal metaplasia at 3 weeks. Transitions from these islands of metaplasia to cholangiofibrosis were commonly seen. The importance of small intestinal metaplasia of oval cells in the genesis of cholangiofibrosis is presented and discussed.

2-Acetylaminofluorene↗
PubMed1985

Initiation and selection of resistant hepatocyte nodules in rats given the pyrrolizidine alkaloids lasiocarpine and senecionine.

The biological mechanisms by which pyrrolizidine alkaloids contribute to initiation and nodule selection (promotion) steps in hepatic carcinogenesis were studied in male Fischer 344 rats. Lasiocarpine at single or double dosages (up to 80 mumol/kg) delayed hepatic regeneration for at least 8 weeks after partial hepatectomy (PH). This regimen of lasiocarpine and PH had a strong selective influence on the growth of gamma-glutamyltranspeptidase (gamma-GT)-positive hepatocyte nodules in rats previously initiated with diethylnitrosamine. However, both lasiocarpine (up to 80 mumol/kg) and senecionine (up to 160 mumol/kg) were inactive as initiators of gamma-GT-positive nodules in rats exposed to a similar selection regimen consisting of 2-acetylaminofluorene and PH. When lasiocarpine or senecionine was given 12 h after PH, very few nodules were initiated. Lasiocarpine pretreatments reduced the initiating activity of diethylnitrosamine and N-nitrosomethylurea in rats subsequently selected with 2-acetylaminofluorene and PH. Resistant nodules selected with lasiocarpine had the typical resistant nodule phenotype (positive for gamma-GT and epoxide hydrolase) and also lacked pyrrolizidine alkaloid-induced megalocytosis. Lasiocarpine treatment also resulted in small regenerative nodular proliferations of hepatocytes that were distinct from resistant nodules because they were negative for gamma-GT and epoxide hydrolase and unrelated to diethylnitrosamine pretreatments. These studies suggest that the hepatocarcinogenicity of pyrrolizidine alkaloids can be better explained by their strong selection (promotion) influence on initiated hepatocytes, rather than by their very weak initiating activity.

Animals↗
PubMed1984

Comparative influences of different PB-type and 3-MC-type polychlorinated biphenyl-induced phenotypes on cytocidal hepatotoxicity of bromobenzene and acetaminophen.

The influences of in vivo treatment with two pure PCB congeners, 2,2',4,4',5,5'-hexachlorobiphenyl (HCBP) and 3,3',4,4'-tetrachlorobiphenyl (TCBP), on the lethal cytotoxicity of bromobenzene and acetaminophen were examined in short-term primary cultures of isolated rat hepatocytes. Lethal injury was measured by release of lactate dehydrogenase (LDH) into culture medium after 20 hr exposure to the hepatotoxins. The HCBP, a PB-type inducer of cytochrome P-450, resembled phenobarbitone (PB) in its ability to increase susceptibility of hepatocytes to bromobenzene (0.5 to 1.6 mM) and acetaminophen (1 to 16 mM). This induced sensitivity was consistently inhibited by SKF-525-A (10 microM) but not alpha-naphthoflavone (ANF, 10 microM) in culture. The 3,3',4,4'-TCPB, a 3-MC-type inducer of cytochrome P-450, resembled 3-methylcholanthrene (3-MC) in its inability to induce susceptibility to bromobenzene. TCBP and 3-MC each increased (20- to 30-fold) cytotoxicity of acetaminophen by a mechanism substantially inhibitable by ANF but not SKF-525-A. These results demonstrate that categorizing pure PCB isomers and congeners into groups according to their different induction capabilities is predictive for their ability to modulate acute hepatocellular necrosis by bromobenzene and acetaminophen.

Acetaminophen↗
PubMed1984

Rapid lipid peroxidation in the nuclear fraction of rat liver induced by a diet deficient in choline and methionine.

A diet deficient in choline and methionine, known to produce hepatocellular carcinoma in the absence of any added chemical carcinogen, induced lipid peroxidation in the nuclear fraction of the liver when fed to male Fischer 344 rats. This lipid peroxidation was detected within 1 day of feeding the diet by the appearance of diene conjugates and increased progressively up to 3 days. It was prevented completely by the addition of choline chloride to the diet. The close proximity of DNA may make it a possible target for attack by free radicals.

Animals↗
PubMed1984

Influences of various xenobiotic inducers on cytocidal toxicity of lasiocarpine and senecionine in primary cultures of rat hepatocytes.

The influences of in vivo pretreatment with phenobarbitone (PB), 3-methylcholanthrene (3-MC), 2,2',4,4',5,5'-hexachlorobiphenyl (HCBP), and 3,3',4,4'-tetrachlorobiphenyl (TCBP) on cytocidal hepatotoxicity of two pyrrolizidine alkaloids, lasiocarpine (LC) and senecionine (SC), were compared in short-term primary cultures of rat hepatocytes. Toxicity was measured by release of lactate dehydrogenase (LDH) into culture medium at 24 h. LC was slightly more toxic to control hepatocytes than SC in the graded response range of 10-160 microM. PB and HCBP (a PB-type polychlorobiphenyl inducer) similarly potentiated toxicity of SC, and each diminished the degree to which cell killing by LC and SC was inhibited by SKF-525-A. By comparison, 3-MC and TCBP (a 3-MC-type PCB inducer) each diminished toxicity of SC but had little effect on toxicity of LC. Alpha-naphthoflavone (ANF) potentiated toxicity of both LC and SC in hepatocytes induced by 3-MC or TCBP but had little effect on responses of hepatocytes induced by either PB or HDBP. These results indicate that xenobiotics that induce similar patterns of cytochrome P-450 isozymes have qualitatively similar modulating influences on cytocidal hepatotoxicity of pyrrolizidine alkaloids in primary cultures. However, the observed modulating effects could not be explained solely on the basis of altered activation rates by the cytochrome P-450 species known to be induced by the various xenobiotics.

Animals↗