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Biomedical subjects

J I Goodman

Publications and source records attributed to J I Goodman.

At least 73 records · Page 4Linked to original sources
PubMed1983

Cell specificity in DNA binding and repair of chemical carcinogens.

Many animal models for organ specific neoplasia have been developed and used to study the pathogenesis of cancer. Morphologic studies have usually concentrated on the response of target cells, whereas biochemical investigations have usually employed whole organ homogenates. Since hepatocytes comprise nearly 90% of the liver's mass and 70-80% of its DNA, alterations in DNA replication, covalent binding and DNA repair of nonparenchymal cells are usually obscured when whole organ homogenates are used. By utilizing cell separation methods, we have been able to demonstrate differences between hepatocyte and nonparenchymal cell replication. DNA damage and repair following exposure to a variety of hepatocarcinogen. Differences in removal of simple O6-alkylguanine and DNA replication correlate with cell specific carcinogenesis of simply alkylating agents. For several other procarcinogens, including 2-acetylaminofluorene and dinitroluene, cell specificity appears to reside primarily in the differential metabolic competence of hepatocytes and nonparenchymal cells. This results in greater covalent binding of the carcinogen to hepatocyte DNA, although the DNA adducts are removed at a similar rate in both cell types.

2-Acetylaminofluorene↗
PubMed1982

Polybrominated biphenyls as promoters in experimental hepatocarcinogenesis in rats.

Female Sprague Dawley rats were fed polybrominated biphenyls (PBB) for six months after a 70% partial hepatectomy and diethylnitrosamine administration (10 mg/kg body weight) to determine if PBB could serve as a tumor promoter in a two stage hepatocarcinogenesis test system. Firemaster BP-6, a commercial mixture of PBB, and its major congener, 2,2',4,4',5,5'-hexabromobiphenyl (HBB) were used in this study. Tumor promoting ability was assessed by measuring enzyme altered foci exhibiting gamma glutamyl transpeptidase activity. Dietary concentrations of 10 and 100 p.p.m. of the mixture of PBB and of HBB were found to be promoters of hepatocarcinogenesis. The mixture of PBB had a greater tumor promoting ability than HBB.

Acyltransferases↗
PubMed1981

Factors influencing the binding of N-2-fluorenylacetamide to specific regions of the hepatic genome in vivo in rats.

The initial binding of N-fluorenylacetamide (2-FAA) and its N-hydroxy metabolite N-hydroxyl-N-2-fluorenylacetamide (N-OH-2-FAA) within the hepatic genome and the effect of ingestion of a 2-FAA-containing (0.05% wt/wt) diet on this binding were examined in the male noninbred Sprague-Dawley rat. Ingestion of 2-FAA for 2 weeks reduced the amount of newly bound carcinogen up to 80%. The extent of this decrease was significantly greater in rats treated with a single injection of 2-FAA when compared to one of N-OH-2-FAA. The distribution of carcinogen within the genome was measured after fractionation of chromatin by DNase II digestion followed by selective MgCl2 precipitation. Two hours after a single injection of N-OH-2-FAA, the amount of carcinogen bound per milligram DNA in the presumed template-active chromatin fraction was 16 times that bound to DNA of the presumed template-repressed chromatin fraction. The amount bound to DNA in the nuclease-resistant chromatin was equal to that observed in the DNA of the presumed template-active fraction. Most (85%) of the total bound carcinogen was located on less than 25% of the total DNA. Evaluation of the amount of carcinogen bound to the N-2 or C-8 positions of guanine demonstrated a significant inverse correlation between the amount bound to a DNA fragment and the percent of that binding occurring at the N-2 position. DNA of the repressed chromatin fraction had the largest N-2/C-8 ratio when compared to the ratios seen in both the expressed chromatin and the nuclease-resistant chromatin DNA. Pretreatment of rats with 2-FAA when compared to one of N-OH-2-FAA. The distribution of carcinogen within the genome was measured after fractionation of 66:667-672.

2-Acetylaminofluorene↗
PubMed1980

A method for the rapid quantitation of methylated hepatic DNA-purines using high pressure liquid chromatography.

An isocratic high pressure liquid chromatography system that can be employed for the separation and quantitation of four of the major methylated purines commonly found in DNA after exposure to carcinogenic/mutagenic alkylating agents (1-methyladenine, 3-methyladenine, O6-methylguanine and 7-methylguanine) is presented in this paper. Data from experiments in which rats were treated with methyl-N-nitrosourea have been used to illustrate the applicability of the method. The amounts of the methylated bases observed were consistent with values reported in the literature.

Alkylating Agents↗
PubMed1980

Inhibition of N-2-fluorenylacetamide-induced mammary tumorigenesis in rats by dietary polybrominated biphenyls.

Female SD rats were maintained for approximately 1 year on diets containing 300 ppm N-2-fluorenylacetamide (2-FAA), 50 ppm polybrominated biphenyls (PBB), or a combination of these chemicals (PBB + 2-FAA). Ingestion of 2-FAA significantly reduced the average survival time of the rats; this effect was virtually blocked by the simultaneous ingestion of PBB. Simultaneous ingestion of PBB also significantly reduced the overall incidence of 2-FAA-induced tumors during the examination period. The lower incidence of tumorigenesis was accompanied by an increase in the latency time for tumor induction; tumors were found in 100% of the animals given 2-FAA after 29 weeks of carcinogen ingestion, whereas only 50% of the PBB + 2-FAA-fed animals had tumors at the end of the experiment (53 wk of carcinogen ingestion). PBB significantly reduced the incidence of 2-FAA-induced tumors at nonhepatic locations (mammary gland and ear duct) but did not affect the incidence of hepatic tumors to a statistically significant extent. PBB ingestion did not significantly increase the incidence of tumors when compared with controls; 1 tumor was found in 1 of 12 rats fed 50 ppm PBB for 57 weeks, and no tumors were detected in 8 controls.

2-Acetylaminofluorene↗
PubMed1979

Quantitative and qualitative aspects of the binding of N-hydroxy-2-acetylaminofluorene to hepatic chromatin fractions.

The binding of a chemical carcinogen to components of hepatic chromatin in male rats was examined. After a single injection of N-[3H]hydroxy-2-acetylaminofluorene ([3H]OH-AAF) covalent binding to chromatin RNA, protein, and DNA occurs. The amount of carcinogen bound to RNA was approximately 5 times greater than to DNA, and 10 times that of the protein. However, loss of carcinogen from RNA with time was rapid, whereas a persistent binding to DNA equal to 15% of the initial values was observed. To localize the initial and persistent DNA-bound carcinogen, the genome was fractionated using two different chromatin fractionation procedures. The procedures used yielded 3 chromatin fractions based on physical characteristics, degree of association with nascent RNA and in vitro template capacity. Based on those parameters, these chromatin fractions have been tentatively classified as template expressed euchromatin, a repressed heterochromatin, and a highly condensed pelleted heterochromatin. With both the glycerol gradient chromatin fractionation procedure and the selective MgCl2 chromatin precipitation procedure, the initial (2 h) binding of carcinogen was greatest on the euchromatin DNA. Loss of carcinogen from the DNA, however, was also significantly faster from the euchromatin when compared to the heterochromatin and the pelleted heterochromatin. By 10 days after a single injection of the carcinogen, the largest amount of bound fluorene residues was located on the pelleted heterochromatin DNA, an apparently repressed portion of the genome, while less than 5% of the initial values were found on either the eu- or heterochromatin. When the rats were fed a 2-acetylaminofluorene-containing diet, loss of carcinogen from the pelleted heterochromatin DNA was enhanced, while loss from the euchromatin DNA was reduced. The covalent nature of the carcinogen modification of DNA was confirmed by thin-layer chromatography (TLC). These studies also demonstrated 2 separate carcinogen-purine base adducts which were identified as N-(guanin-8-yl)-N-AF and 3-(guanin-N2-yl)-N-AAF based on either co-chromatography with an authentic standard or on published Rf-values, respectively. The pelleted heterochromatin DNA had a significantly greater proportion of the 3-guanine-N2 adduct when compared to DNA from either the eu- or heterochromatin.

2-Acetylaminofluorene↗
PubMed1979

Non-random nature of 2-acetylaminofluorene-induced alterations of DNA template capacity.

Male rats were fed a diet containing 0.03% (w/w) 2-acetylaminofluorene (AAF) and their hepatic DNA was isolated and transcribed with E. coli RNA polymerase. Ingestion of the carcinogen-containing diet for 4 days substantially reduced the template capacity of the isolated DNA. This reduction in template capacity was due to an apparent decreased RNA chain size (up to 50%), with no significant changes in initiation or re-initiation of RNA synthesis. This premature termination of RNA synthesis was accompanied, in some instances, by a reduced rate of RNA chain elongation. When the rats were returned to a basal diet for 7 days following 4 days of AAF ingestion, template capacity and RNA chain size returned to control values. Fractionation of hepatic chromatin on a glycerol gradient revealed that inhibition of DNA template capacity occurs on portions exhibiting characteristics of expressed, as well as those with characteristics of repressed, segments of the genome. In contrast, the DNA isolated from a small, highly condensed chromatin fraction (15% of total chromatin-DNA) showed no significant reduction in total template capacity. Analysis of the fidelity of RNA synthesis on this DNA template was performed by determining the rate of addition of individual nucleotide triphosphates to a growing RNA chain. Large reductions in the rates of adenosine and uridine polymerization were observed while no changes in guanosine or cytidine polymerization were found. This suggests the presence of functionally significant carcinogen-induced modifications of adenine. The inhibition in the rate of adenosine and uridine polymerization was reversed when the animals were placed on a basal diet after AAF ingestion.

2-Acetylaminofluorene↗
PubMed1976

Studies on the mechanism of inhibition of 2-acetylaminofluorene toxicity by butylated hydroxytoluene.

Male rats were placed on a diet containing 0.05% (w/w) of the hepatic carcinogen 2-acetylaminofluorene (AAF). They ceased to gain weight. However, when the carcinogenic diet was supplemented with butylated hydroxytoluene (BHT) (0.5% w/w), an antioxidant, the animals gained weight at approximately one-half of the normal rate. This observation led to a series of experiments aimed at elucidating the mechanism(s) by which BHT reduced the toxicity of AAF. These initial studies were directed towards the effect of BHT on the extent and duration of the covalent binding of AAF with DNA. BHT feeding was shown to reduce the binding of carcinogen to hepatic DNA. Studies employing cells in culture demonstrated that BHT does not influence either excision repair or post-replication repair of DNA. These data indicate that a potential mechanism of action of BHT is at the anti-initiation level of carcinogen-induced DNA damage.

2-Acetylaminofluorene↗