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At least 19 recordsLinked to original sources
PubMed1979

Effect of pH on the ratio of substitution products in DNA after reaction with the carcinogen N-acetoxy-2-acetylaminofluorene.

The substitution reaction products of N-acetoxy-2-acetylaminofluorene (N-AcO-AAF) and the N-sulfate (potassium salt) of N-hydroxy-4-acetyl-aminobiphenyl (N-OSO3K-AABP) with DNA from calf thymus were determined after reaction in buffered solutions of 0.10 M NaCl at pH values from 4--9. In the case of N-AcO-AAF, the ratio of N-(guanin-8-yl)-2-acetylaminofluorene (N-(guanine-8-yl)-AAF) to 3-(guanin-N2-yl)-2-acetylaminofluorene (3-(guanin-N2-yl)-AAF) increased 2.2 times over the entire pH range studied, starting at pH 9. With the N-OSO3K-AABP, the total substitution of guanine was much lower (22--34 times) as compared with N-AcO-AAF, and the ratio of N-(guanin-8-yl)-4-acetylaminobiphenyl to 3-(guanin-N2-yl)-4-acetylaminobiphenyl was not affected by a change in pH of the reaction medium. As expected, heat-denatured DNA reacted more extensively with both esters, but an increase in substitution was much more pronounced for the biphenyl derivative (9 times) than for the fluorene compound (2.8 times). Degradation, denaturation or interstrand cross-linking of DNA were not observed under the reaction conditions employed.

2-Acetylaminofluorene↗
PubMedDate not supplied

Oxidative biotransformation of 2-acetylaminofluorene in fetal and placental tissues of humans and monkeys. Correlations with aryl hydrocarbon hydroxylase activities.

The mixed-function oxidation of 14C-labled 2-acetylaminofluorene (AAF) was investigated in placental and fetal tissues of humans and monkeys (Macaca nemestrina) in vitro. The major metabolite formed in most tissues was 7-hydroxy-AAF. Rates of the hydroxylation reactions varied widely among the tissues investigated and were generally one to two orders of magnitude lower than those measured in rat hepatic tissues. High correlations among rates of 7-,5-, and 3- and between 1- and N-hydroxylations of AAF were observed. The latter two reactions were less responsive to inhibition by carbon monoxide. Rates of 3-hydroxylations of benzo[a]pyrene (BP) also were highly correlated with rates of 7-, 5-, and 3-hydroxylations of AAF but were not correlated with rates of 1- and N-hydroxylations in human placental microsomes. A lack of statistically significant correlations was observed among rates of many of these hydroxylation reactions studied in primate fetal tissues. Rates of 7-, 5-, and 3-hydroxylations of AAF were not statistically correlated with rates of 3-hydroxylation of BP in homogenates of primate fetal tissues in most instances, but statistically significant correlations among rates of 3-hydroxylation of BP and 1- and N-hydroxylations of AAF were observed in those preparations. The results suggested two separate mechanisms for the genetic control of rates of placental aromatic ring- and N-hydroxylation reactions as opposed to apparent multiple genetic controls for rates of these hydroxylation reactions in primate fetal tissues.

2-Acetylaminofluorene↗
PubMed1977

Adduct formation between the carcinogen N-acetoxy-2-acetylaminofluorene and synthetic polydeoxyribonucleotides.

The chemical carcinogen N-acetoxy-2-acetylaminofluorene (NA-AAF) was reacted with poly(dG-dC) - poly(dG-dC); poly dG - poly dC; poly(dA-dT) - poly (dA-dT); and poly dA - poly dT under a variety of conditions. Poly (dG-homo GC polymer and 10--20 more reactive the A + T polymers. Lowering the ionic strength increased the extent of reaction, while pH change (8.9 vs. 5.5) had only a small effect. If ionic strength was adjusted so that the two guanine-containing polymers showed equal thermal stability (as judged by Tm) then the alternating copolymer was 7 times as reactive as the homopolymer. In aggreement with previous investigators, the major product was found to be 8-(N-2-fluorenylacetamido) deoxyguanosine.

Acetoxyacetylaminofluorene↗
PubMed1976

Purification and characterization of N-hydroxy-2-acetylaminofluorene sulfotransferase from rat liver.

N-Hydroxy-2-acetylaminofluorene (N-OH-2-AAF) sulfotransferase is an enzyme that catalyzes the sulfate transfer from the active sulfate, 3'-phosphoadenosine 5'-phosphosulfate (PAPS), to N-OH-2-AAF to form a highly reactive product acetylaminofluorene N-sulfate. It has been purified about 2000-fold with a yield of over 12% from adult Sprague-Dawley male rat livers by an eight-step procedure. The final preparation was homogeneous on analytrical disc gel electrophoresis. The purified enzyme had activity toward p-nitrophenol with an approximately 1600-fold increase in specific activity over the crude homogenate, but it had almost no detectable activity toward steroids such as estrone, beta-estradiol, testosterone, dehydroisoandrosterone, and corticosterone. There was also very little sulfation activity toward serotonin and L-tyrosine methyl ester. The optimal pH for the enzyme activity is approximately 6.3 when measured in sodium phosphate buffer. Mg2+ at 6 to 9 mM could increase the enzyme activity up to 30%. Mn2+ activated the enzyme only slightly at very low concentrations. Zn2+, Co2+, Cu2+, and Ni2+ were all strongly inhibitory, but Ca2+ had very little effect. Thiol compounds were found to have a stabilizing effect and thiol-blocking reagents were potent inhibitors for this enzyme. The pure enzyme was very unstable especially in diluet solutions. The isoelectric point (pl) of the enzyme is 5.66 +/- 0.07. The molecular weight of the native enzyme was 68,000 +/- 500 as estimated by Sephadex G-100 and G-200 gel filtrations. A single component with molecular weight of 38,250 +/- 1,350 was observed on sodium dodecyl sulfate gel electrophoresis in the absence and presence of 2-mercaptoethanol. Comparison of the enzyme activity in mail and female rat livers at each stage of purification revealed that there was only a trace amount of N-OH-2-AAF sulfotransferase present in the female rat liver.

Animals↗
PubMed1976

Enzymic deacetylation of carcinogenic arylacetamides by tissue microsomes of the dog and other species.

The relative ability of arylacetamide deacetylase enzyme systems of dog liver to carry out the deacetylation of the carcinogens, 4-acetylaminobiphenyl, 2-acetylaminofluorene, and 2-acetylaminaphthalene, was examined. The arylacetamides were incubated with unfortified dog liver microsomes, and enzyme activity (nmol arylamine/mg protein/hr) was estimated by colorimetric quantitation of the resulting arylamines. The dog liver enzyme system displayed characteristics similar to those described for the rodent liver enzyme system in that enzyme activity was greatest in liver tissue, was localized in the microsomal subcellular fraction, required no cofactors, and was inhibited by heat, sodium fluoride, and thiol reagents. In five replicate assays, the relative rates of deacetylation were about 10, 6, and 1 with 4-acetylaminobiphenyl (84.8 +/- 12.4), 2-acetylaminofluorene (52.5 +/- 5.1), and 2-acetylaminonaphthalene (8.8 +/- 3.3), respectively. As a canine urinary bladder carcinogen, 4-acetylaminobiphenyl is considered more potent than 2-acetylaminofluroene, while 2-acetylaminonaphthalene is devoid of detectable carcinogenic activity, despite the fact that 2-aminoaphthalene is a well-established canine urinary bladder carcinogen. Removal of the acetyl group may be a requirement for urinary bladder carcinogenesis; accordingly, the present studies demonstrate the appearance of a direct relationship between dog liver deacetylase enzyme specificity and urinary bladder susceptibility to these carcinogenic arylacetamides.

2-Acetylaminofluorene↗
PubMed1976

Glutathione and gamma glutamyl transpeptidase in rat liver during chemical carcinogenesis.

Continued administration of several hepatocarcinogens led to an increase in the concentration of glutathione (GSH) in the livers of intact, but not of hypophysectomized or adrenalectomized rats. The concentration of GSH remained high untill the development of hyperplastic nodules. Subsequently, the concentration of GSH dropped to the normal level or below. A single dose of 3'-methyl-4-dimethylaminoazobenzene (3'-Me-DAB) produced an increase of GSH which, within a certain range, depended upon the amount of the carcinogen. In well differentiated, slowly growing hepatomas, the concentration of GSH approached the level in normal adult rat liver. On the other hand, in nondifferentiated and rapidly growing hepatomas, GSH was only 30-40% of that in normal liver. The activity of gamma-glutamyl transpeptidase (GTase) increased within 24-48 hours after a single large dose of 3'-Me-DAB. Continued feeding of 3'-Me-DAB led to an exponential increase of GTase. During hepatocarcinogenesis, the level of GTase activity corresponded to the degree and size of pathologic changes produced in rat liver. Chloramphenicol partially inhibited the increase of GTase induced by 2-acetylaminofluorene. Pretreatment with 3-methylcholanthrene partially inhibited the increase of GTase that had been induced by a single dose of 3'-Me-DAB. Puromycin partially inhibited the increase of GTase induced by several doses of dimethylnitrosamine. These observations indicated a close connection between the activation of GTase and chemical carcinogenesis in rat liver. Measurements of GTase activity in 12 Morris hepatomas supported this conclusion; their GTase levels were greatly elevated compared with that in normal adult rat liver.

2-Acetylaminofluorene↗
PubMed1977

Rapid emergence of carcinogen-induced hyperplastic lesions in a new model for the sequential analysis of liver carcinogenesis.

Hyperplastic liver lesions which develop following administration of hepatocarcinogens have been implicated as probable precursors for the cancers which ultimately develop. Some, and possibly all, of these putative precursor lesions are resistant to the necrogenic and growth-inhibitory action of hepatocarcinogens and other hepatotoxins. An in vivo assay system based on this resistance phenomenon has been developed which encourages the rapid selective growth of carcinogen-altered hepatocytes, facilitating their early identification. The system consists of a) single carcinogenic dose of diethylnitrosamine (DEN), b) short-term dietary exposure to 2-acetylaminofluorene (2-AAF) sufficient to suppress growth of virtually all normal hepatocytes, and c) partial hepatectomy (PH) to actuate rapid growth of DEN-altered hepatocytes not suppressed by 2-AAF. Following PH, the DEN-altered hepatocytes grow out as basophilic foci which are distributed randomly throughout the 2-AAF-suppressed parenchyma. Within 1 week they can be seen as tiny, discrete, translucent nodules on the capsular and cut surface of the remaining lobes. The lesions continue to proliferate and become histologically indistinguishable from typical carcinogen-induced hyperplastic liver nodules frequently described in the literature. These in turn appear to be precursor lesions for at least some hepatocellular carcinomas. Future experimentation based on this phenomenon of "selective resistance to cytotoxicity" should prove valuable in answering specific questions about the carcinogenic process in liver and possibly in other tissues.

2-Acetylaminofluorene↗
PubMed1978

Gamma-glutamyltransferase in putative premalignant liver cell populations during hepatocarcinogenesis.

The activity of gamma-glutamyltransferase, as measured quantitatively and by histochemical staining, was studied in different cell populations during the induction of liver cancer with 2-acetylaminofluorene (2-AAF) or diethylnitrosamine and compared with findings in fetal and in intact and regenerating adult liver. The enzyme activity is 20-fold higher in 12-week nodules than in control livers and 30-fold higher in 20-week nodules than in controls. A similar 30-fold increase in activity relative to control is present in hepatomas, induced by either 2-AAF or diethylnitrosamine, and in fetal hepatocytes. The enzyme shows increases in activity in foci of very early putative preneoplastic hepatocytes induced by a single dose of diethylnitrosamine and selected by low doses of 2-AAF plus partial hepatectomy. By 7 days, the foci show a 4-fold increase in enzyme activity, and by 3 weeks they are 40-fold higher than in the control liver. Histochemically, the foci are strongly positive for gamma-glutamyltransferase, especially in the bile canaliculi. By 21 days, the ductular (oval) cells induced by 2-AAF have disappeared. When stained for the enzyme activity, the foci stand out clearly against the negative background of the liver, allowing easy quantitation. It appears that gamma-glutamyltransferase is a useful marker for preneoplastic hepatocytes.

2-Acetylaminofluorene↗
PubMed1978

Transfer of viable putative preneoplastic hepatocytes to the livers of syngeneic host rats.

A new approach was developed by which freshly isolated, chemical carcinogen-altered hepatocytes with the positive marker gamma-glutamyl transpeptidase (gamma-GT) could be transferred from adult donor F344 rats to the livers of syngeneic, adult host rats. Selective proliferation of gamma-GT-positive hepatocytes was induced in host rat livers, such that large, macroscopic colonies of altered hepatocytes could be generated within 10 days of the cell transfer operation. Quantitation of the number of gamma-GT-positive hepatocyte colonies (foci) appearing per square centimeter of host liver section area on day 10 following cell transfer revealed that prior treatment of host rats with a low dose of 2-acetylaminofluorene was essential for the appearance of large numbers of foci. In addition, the appearance of foci on day 10 depended on the presence of intact, gamma-GT-positive hepatocytes in the infused (transferred) cell suspensions.

2-Acetylaminofluorene↗