Chemistry, Carcinogenicity, and Metabolism of 2-Fluorenamine and Related Compounds

Weisburger, Elizabeth K.; Weisburger, John H.

doi:10.1016/s0065-230x(08)60415-7

Cited by 164 publications

(18 citation statements)

References 199 publications

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“…2-Acetylaminofluorene (AAF) is a potent carcinogen to the rat liver (38,39), where it undergoes bioactivation to a DNA-reactive ultimate carcinogen (48). In Fischer-344 (F-344) male rats, administration of AAF produces a rapid appearance of hepatocellular altered foci in the liver characterized by a variety of abnormalities (10, 15, 16, 18-20, 35, 40, 46, 49).…”

Section: Introductionmentioning

confidence: 99%

Sequential Functional and Morphological Alterations During Hepatocarcinogenesis Induced in Rats by Feeding of a Low Dose of 2-Acetylaminofluorene

et al. 1994

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The early cellular events in liver carcinogenesis were studied in Fischer-344 male rats that either were fed 200 ppm 2-acetylaminofluorene (AAF) for up to 10 wk or were fed the carcinogen for 8 wk, the number again increased. IS -characterized the majority of foci during carcinogen administration, whereas after cessation of exposure, GGT+ and PGT+ foci predominated. None of the foci were positive for GS. After AAF exposure for 10 wk, a few neoplasms developed and greater numbers occurred after maintenance for a further 24 wk of rats exposed for 8 wk. We conclude the following: (a) the low dose of AAF caused subtle alterations in function and proliferation of normal hepatocytes and converted hepatocytes into focus cells; (b) reduction of the GS+ area is a sensitive indicator of cytotoxicity of AAF; (c) the development of some foci at an early stage depends on a promoting action of AAF, which ceased when the carcinogen was withdrawn, allowing some foci to undergo reversion; (d) a strong linkage exists in expression of IS-, GGT+, and PGT+ in foci; (e) the carcinogenic process accelerates in the absence of any indication of increased cytotoxicity by AAF; and (f) under the conditions of this study, no GS+ foci, adenomas, and carcinomas were found, indicating that no carcinogen-induced expression of GS occurred in these lesions and that GS expression is not linked to other phenotypic abnormalities.

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Section: Introductionmentioning

confidence: 99%

Sequential Functional and Morphological Alterations During Hepatocarcinogenesis Induced in Rats by Feeding of a Low Dose of 2-Acetylaminofluorene

et al. 1994

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“…Pour plates were prepared as described in Methods, incorporating into the top agar TA1538, [5][6][7][8][9][10] MlI of test solution, and 0.5 ml of 8-9 Mix containing various amounts of 8-9 as indicated.…”

Section: Resultsmentioning

confidence: 99%

A Simple Method for the Detection of Mutagens in Urine: Studies with the Carcinogen 2-Acetylaminofluorene

Durston¹,

Ames²

1974

Proc. Natl. Acad. Sci. U.S.A.

124

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We described previously a simple test on petri plates for detecting many carcinogens as mutagens using an especially sensitive set of bacterial strains to detect mutagens and a rat, or human, liver homogenate for carcinogen activation. We now extend the utility of the method for the detection of mutagenic metabolites in urine. The addition of commercial 6-glucuronidase (EC 3.2.1.31) to the petri plates along with the urine, liver homogenate, and bacteria allows detection of metabolites that are excreted in urine as jB-glucuronide conjugates.By this method mutagenic activity is readily demonstrated with urine of rats that were administered as little as 200 jug (1.6 mg/kg) of the carcinogen, 2-acetylaminofluorene.In this case the major urinary metabolite that we detect appears to be a glucuronide conjugate. We propose that the method be used for the screening of human urines in order to detect mutagenic metabolites of drugs and of dietary components. It may also be useful for testing of urinary metabolites of drugs and food additives in experimental animals.We have previously described a very sensitive and simple bacterial test system for detecting chemical mutagens (1-4). The compounds are tested on petri plates with specially constructed mutants of Salmonella typimurium as tester strains. Four tester strains have been selected for sensitivity and specificity in being reverted from a histidine requirement back to prototrophy by a variety of mutagens. One strain can be used to detect mutagens causing base-pair substitutions and three to detect various kinds of frameshift mutagens. In addition to the histidine mutation, each tester strain has two additional mutations that greatly increase their sensitivity to mutagens: one causes loss of the excision repair system and the other loss of the lipopolysaccharide barrier that coats the surface of the bacteria. We have shown that by adding a microsomal activation system of rat (or human) liver to the petri plates a wide variety of carcinogens can be activated to mutagens and thus detected easily (3). Thus, an important aspect of mammalian metabolism can be duplicated in an in vitro test. The present study examines the testing of urine in the combined bacterial/liver system. A wide variety of metabolites of drugs and other ingested compounds appear in the urine. Since many metabolites are excreted in urine as glucuronides, we added fl-glucuronidase (EC 3.2.1.31) to our test plates. The method is demonstrated by administering the carcinogen, 2-acetylaminofluorene (AcAF), to rats and detecting mutagenic metabolites in the urine.AcAF, like many other compounds, gives rise to a large number of metabolites (5-li). The oxidation products Nhydro.xy-2-acetylaminofluorene (N-OH-AcAF), N-hydroxy-2-aminofluorene (N-OH-AF), and 2-nitrosofluorene (NOF), are thought to be proximate or ultimate carcinogens formed from AcAF and 2-aminofluorene (AF) by the microsomal systems of liver (5). They are more carcinogenic than the parent compounds at the site of application in rodents an...

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“…These include 2-amino-and 2-acetamido-fluorene (Weisburger and Weisburger, 1958), urethane (Cowen, 1950 and implanted plastic film (Stinson, 1960). There are also reports on the rarity of spontaneous tumours in the guinea-pig (Warren and Gates, 1941;Lombard, 1960;Mosinger, 1961).…”

Section: Discussionmentioning

confidence: 99%

The carcinogenicity of β-propiolactone and 4-nitroquinoline N-oxide for the skin of the guinea-pig.

Parish¹,

Searle²

1966

Br J Cancer

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Chemistry, Carcinogenicity, and Metabolism of 2-Fluorenamine and Related Compounds

Cited by 164 publications

References 199 publications

Sequential Functional and Morphological Alterations During Hepatocarcinogenesis Induced in Rats by Feeding of a Low Dose of 2-Acetylaminofluorene

Sequential Functional and Morphological Alterations During Hepatocarcinogenesis Induced in Rats by Feeding of a Low Dose of 2-Acetylaminofluorene

A Simple Method for the Detection of Mutagens in Urine: Studies with the Carcinogen 2-Acetylaminofluorene

The carcinogenicity of β-propiolactone and 4-nitroquinoline N-oxide for the skin of the guinea-pig.

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