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At least 19 recordsLinked to original sources
PubMed1978

Effects of selenium and retinoic acid on the metabolism of N-acetylaminofluorene and N-hydroxyacetylamino-fluorene.

Male albino rats were given 4 ppm selenium (Se(as Na2SeO3) in the water, or 0.25% retinoic acid was added to the basal diet for 3 days. Control and treated animals were given 17 mg acetylaminofluorene (AAF)-9-14C or N-hydroxyacetylaminofluorene (NOHAAF)-9-14C/kg body wt. The administration of Se enhanced glucuronyl transferase activity by 100% and inhibited p-nitrophenol-sulfotransferase by 50%. Retinoic acid enhanced the glucuronyl transferase 37% and inhibited the p-nitrophenol-sulfotransferase by 50%. Pretreatment with Se lowered levels of both AAF and NOHAAF in liver tissue by 30%. Se administration lowered the binding of the labeled carcinogens, or metabolites thereof, to the liver DNA and tRNA.

2-Acetylaminofluorene↗
PubMed1978

A human subject with a new defect in repair of ultraviolet damage.

The subject under study (11961) is a child with extreme sun sensitivity. Fibroblasts derived from the child's skin, like those from patients with the disorder xeroderma pigmentosum were hypersensitive to the lethal effects of 254 nm and 310 nm UV-irradiation. Unlike xeroderma pigmentosum cells, however, fibroblasts from our subject were not hypersensitive to the chemical mutagen N-hydroxyacetylaminofluorene but they were hypersensitive to ethylmethanesulfonate. Furthermore, despite the ultra violet light sensitivity, no defects could be detected either in excision or postreplication repair of damaged DNA after UV-irradiation of 11961 cells. This again contrasts with xeroderma pigmentosum cells, which are defective in one or the other of these repair processes. On the basis of these characteristics and the clinical symptoms, we are not at present able to classify this patient as having any of the known sun-sensitive syndromes.

Cell Survival↗
PubMed1992

Steroidal nonspecific esterase metabolism of N-hydroxy-2-acetylaminofluorene: evidence for selective activation by the cellular reductant NADPH.

The significance of the nonspecific esterases of human mononuclear leukocytes (HMLs) in arylamine carcinogenesis is suggested by data showing that the metabolically formed hydroxamic acid derivative of 2-acetylaminofluorene, N-hydroxy-2-acetylaminofluorene, is a substrate for this class of enzymes. A viable cell assay for the nonspecific esterases using alpha-naphthyl acetate as substrate is described, and data showing this activity to be sensitive to already known substrates for HML esterases as measured by three previously described assays are presented. All four assays of the same esterase activity are shown to be highly sensitive to up- and down-regulation by addition of NADPH or NADP to viable HML cultures. Selective activation of a purified rabbit nonspecific esterase by NADPH, but not by the other cellular reductants, NADH and glutathione, was demonstrated. Cytosols prepared from normal human tissue samples of liver, breast, colon, and brain were also activated by the presence of NADPH. These data do not indicate that steroidal nonspecific esterases are redox-modulated by the presence of mixed disulfides in their structure. Instead, they support the direct and specific influence of NADPH as a widespread activator of esterase activity by a mechanism not yet understood.

Animals↗
PubMed1992

Activation of the Ki-ras gene in spontaneous and chemically induced lung tumors in CD-1 mice.

As part of an evaluation of the effectiveness of using ras mutation analysis for distinguishing carcinogen-induced from spontaneous tumors, we examined the profile of ras gene point mutations in spontaneous, 7,12-dimethylbenz[a]anthracene (DMBA)-induced, and N-nitrosodiethylamine (DEN)-induced lung tumors from Crl:CD-1(ICR)BR (CD-1) mice. Although all of the lung tumors were assayed for mutations in the Ha-ras, Ki-ras, and N-ras genes (codons 12, 13, and 61), only Ki-ras mutations were found, which is consistent with other studies that have noted a strong preference for Ki-ras gene activation in mouse, rat, and human lung tumors. We found that spontaneous CD-1 mouse lung tumors had a very high frequency of Ki-ras gene activation (17 of 20 tumors; 85%), distributed among codons 12 (5 of 20), 13 (1 of 20), and 61 (11 of 20). DMBA-induced lung tumors had a slightly higher frequency of Ki-ras gene mutations (16 of 16; 100%), again distributed among codons 12 (5 of 16), 13 (2 of 16), and 61 (9 of 16). However, seven of the DMBA tumors had mutations qualitatively different from those found in spontaneous tumors. In contrast to DMBA-induced tumors, DEN-induced tumors had a lower frequency of Ki-ras mutations (36%) when compared with spontaneous lung tumors, suggesting that DEN primarily induces lung carcinogenesis by a mechanism other than ras gene activation. Thus, although spontaneous and induced CD-1 mouse lung tumors have a strong tissue-specific preference for carrying an activated Ki-ras gene, the nature of the initiating carcinogen can influence the frequency or profile of Ki-ras mutations.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1978

Activation of the carcinogen N-hydroxy-2-acetylaminofluorene by rat mammary peroxidase.

A peroxidase preparation from rat mammary gland parenchymal cells, a target tissue of arylamine carcinogens, was shown to activate the carcinogen N-hydroxy-2-acetylaminofluorene via a nitroxyl free radical intermediate to the more active carcinogens nitrosofluorene and N-acetoxy-2-acetylaminofluorene. Hydrogen peroxide, cumene hydroperoxide, and linoleic acid hydroperoxide were effective as substrates. The antioxidants ascorbate, propyl gallate and reduced glutathione prevented the free radical activation route.

Animals↗
PubMed1978

Studies on the transformation of rat embryo cells of low passage by carcinogenic fluorenylhydroxamic acids and their acetate esters.

Rat embryo cells of low passage subjected to a single treatment with certain carcinogenic fluorenylhydroxamic acids and their respective acetate esters showed signs of transformation in vitro, such as changes in phenotype, growth in soft agar and agglutination with concanavalin A. In addition, certain changes in karyotype and loss of diploidy were observed. There was no evidence, either by electron microscopy or by assay of RNA-dependent DNA polymerase, for the presence of virus. None of these cell lines produced tumors after inoculation into the isologous host. The results of these study lead us to suggest that malignant transformation is a multistep process and that certain criteria of transformation of rat embryo cells are associated with the initial stage(s) in which the cells are transformed without being tumorigenic. The ultimate test for malignant transformation of rat embryo cells remains the production of tumors in a susceptible host after inoculation of treated cells.

Agglutination Tests↗
PubMed1977

The action of N-hydroxy-2-acetylaminofluorene on the synthesis of ribosomal and poly (A)-RNA in normal and regenerating liver.

Polyribosomal RNA prepared from normal and regenerating liver was chromatographed on poly(U)-Sepharose to obtain rRNA and poly(A)-RNA. Under the conditions employed for labeling the RNA with [5-3H]orotic acid, poly (A)-RNA from regenerating liver represented 1--3% of the total RNA content, and 14--18% of the total radioactivity in polyribosomal RNA at varying times after partial hepatectomy. The specific activity of poly (A)-RNA was elevated by 50% and 30% only at 2 h and 6 h after partial hepatectomy, respectively. Ribosomal RNA synthesis increased 2.5--4 fold at 2--20 h after operation. Treatment of normal or partially hepatectomized rats with N-hydroxy-2-acetylaminofluorene showed a differential dose-dependent effect on rRNA and poly (A)-RNA synthesis with rRNA synthesis being more sensitive to the inhibitory effect of the carcinogen. No change in the poly(A) content was apparent as a result of N-hydroxy-2-acetylaminofluorene treatment.

Animals↗
PubMed1992

Fasting increases the susceptibility of rat hepatocytes to the cytotoxic effects of N-hydroxy-acetylaminofluorene. Effects on mitochondrial respiration and membrane potential.

Isolated rat hepatocytes were incubated with the carcinogen N-hydroxy-2-acetylaminofluorene (N-OH-AAF). Cells from fasted rats were much more susceptible to the cytotoxic effects of 1 mM N-OH-AAF than cells from fed rats: after approximately 90 min exposure the former were all dead but the latter still viable. Even after 240 min 25% of the "fed" cells were still viable. The loss of viability was preceded by a decrease in mitochondrial membrane potential (MMP) and inhibition of respiration; the mitochondrial respiration as measured in permeabilized cells appeared uncoupled. Addition of 15 mM fructose prevented cell death and the loss of MMP in cells both from fed and fasted rats to a large extent; however, uncoupling was not prevented. After incubation of hepatocytes from fasted rats with 1 mM [3H]N-OH-AAF for 120 min, 12 nmol [3H]N-OH-AAF became bound per mg cell protein. Addition of fructose decreased this to 7 nmol. In cells from fed animals 4 nmol [3H]N-OH-AAF became bound after 120 min, in this case fructose had no effect. Part of the protective effect of fructose might be explained by a decrease in intracellular ATP, which prevents the formation of reactive intermediates of N-OH-AAF resulting in a decrease of covalent binding, in addition, fructose protects via a yet to be determined mechanism.

Adenosine Triphosphate↗
PubMed1975

Evidence for a second arylhydroxamic acid acyltransferase species in the small intestine of the rat.

The small intestine of the Sprague-Dawley rat has been shown to contain two species of arylhydroxamic acid acyltransferases. These enzymes were separable by gel filtration on Sephadex G-100. The smaller species had the mobility of rat liver acyltransferase and was precipitated with antiserum directed against the liver enzyme. The larger species was not precipitated with this antiserum. These species differ in their relative abilities to utilize N-hydroxy-N-2-acetylaminofluorene (N-hydroxy-AAF) and N-hydroxy-N-4-acetylaminobiphenyl (N-hydroxy-AABP) as substrates, and in their inhibition by non immune serum.

Acetyltransferases↗
PubMed1976

Biochemical changes after hepatic injury by allyl alcohol and N-hydroxy-2-acetylaminofluorene.

Administration of hepatotoxic doses of allyl alcohol and N-hydroxy-2-acetylaminofluorene (N-OH-AAF) TO adult male rats produced periportal necrosis and functional derangement of the hepatic endoplasmic reticulum within 24 h. The rates of N-demethylation of ethylmorphine and p-hydroxylation of aniline were decreased 6 h following allyl alcohol administration, but cytochromes P-450 and b5 were unchanged. In contrast, administration of NOH-AAF decreased cytochromes P-450 and b5 and the rate of aniline p-hydroxylation, but did not change the rate of N-demethylation of ethylmorphine or the activities of cytochrome c reductase and glucose-6-phosphatase. No decrease was observed in the activity of the cytosol enzyme, DT diaphorase, following allyl alcohol treatment. The changes by these periportal hepatotoxins were compared with those produced both by central and midzonal hepatotoxins and with changes occurring in the liver after surgical partial hepatectomy.

Acetaminophen↗