Metabolism of the carcinogen N-hydroxy-N-2-fluorenylacetamide in germ-free rats

Weisburger, John H.; Grantham, Preston H.; Horton, Richard E.; Weisburger, Elizabeth K.

doi:10.1016/0006-2952(70)90336-9

Cited by 63 publications

(15 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Although there is no evidence that AOM is metabolized by bacterial or colonic mucosal ␤-glucuronidase, this enzyme is largely responsible for the hydrolysis of glucuronide conjugates in the colon and thus important in the generation of toxic and carcinogenic substances. 30,43 Inhibition of AOM-induced colon tumorigenesis by inhibitors of ␤-glucuronidase was reported in rats. 24,44 Silymarin and its component silybin protect against CCl 4 -induced liver toxicity by inhibiting ␤-glucuronidase activity in the liver and in intestinal bacteria in rats.…”

Section: Discussionmentioning

confidence: 99%

Silymarin, a naturally occurring polyphenolic antioxidant flavonoid, inhibits azoxymethane‐induced colon carcinogenesis in male F344 rats

Kohno

Tanaka

Kawabata

et al. 2002

Intl Journal of Cancer

135

View full text Add to dashboard Cite

The modifying effect of dietary administration of the polyphenolic antioxidant flavonoid silymarin, isolated from milk thistle [Silybum marianum (L.) Gaertneri], on AOM-induced colon carcinogenesis was investigated in male F344 rats. In the short-term study, the effects of silymarin on the development of AOM-induced colonic ACF, being putative precursor lesions for colonic adenocarcinoma, were assayed to predict the modifying effects of dietary silymarin on colon tumorigenesis. Also, the activity of detoxifying enzymes (GST and QR) in liver and colonic mucosa was determined in rats gavaged with silymarin. Subsequently, the possible inhibitory effects of dietary feeding of silymarin on AOM-induced colon carcinogenesis were evaluated using a long-term animal experiment. In the short-term study, dietary administration of silymarin (100, 500 and 1,000 ppm in diet), either during or after carcinogen exposure, for 4 weeks caused significant reduction in the frequency of colonic ACF in a dose-dependent manner. Silymarin given by gavage elevated the activity of detoxifying enzymes in both organs. In the long-term experiment, dietary feeding of silymarin (100 and 500 ppm) during the initiation or postinitiation phase of AOM-induced colon carcinogenesis reduced the incidence and multiplicity of colonic adenocarcinoma. The inhibition by feeding with 500 ppm silymarin was significant (p < 0.05 by initiation feeding and p < 0.01 by postinitiation feeding). Also, silymarin administration in the diet lowered the PCNA labeling index and increased the number of apoptotic cells in adenocarcinoma. ␤-Glucuronidase activity, PGE 2 level and polyamine content were decreased in colonic mucosa. These results clearly indicate a chemopreventive ability of dietary silymarin against chemically induced colon tumorigenesis and will provide a scientific basis for progression to clinical trials of the chemoprevention of human colon cancer. Colorectal cancer is the third most common malignant neoplasm in the world. 1 In Japan, its incidence has been increasing, and it is now the third leading cause of cancer death. In this context, primary prevention, including chemoprevention, is important.Silymarin, the collective name for an extract from milk thistle [Silybum marianum (L.) Gaertneri], 2 is a naturally occurring polyphenolic flavonoid antioxidant. 3 It is composed mainly (-80%, w/w) of silybin (also called silybinin, silibin or silibinin), with smaller amounts of other stereoisomers, such as isosilybin, dihydrosilybin, silydianin and silychristin. 4 Silymarin protects experimental animals against the hepatotoxin ␣-amanitin 2 and has a strong antioxidant property. 5 Other biologic properties of silymarin and its components have been reported, including inhibition of LOX 6 and PG synthetase. 7 For over 20 years, silymarin has been used clinically in Europe for the treatment of alcoholic liver disease and as an antihepatotoxic agent. 8 As a therapeutic agent, it is well tolerated and largely free of adverse effects. 5 It might be a potent antica...

show abstract

Section: Discussionmentioning

confidence: 99%

Silymarin, a naturally occurring polyphenolic antioxidant flavonoid, inhibits azoxymethane‐induced colon carcinogenesis in male F344 rats

Kohno

Tanaka

Kawabata

et al. 2002

Intl Journal of Cancer

135

View full text Add to dashboard Cite

show abstract

“…Gut microbes contained high levels of reductases (Sousa et al, 2008). Weisburger et al (1970) demonstrated gut microbial N-dehydroxylation of a carcinogen (N-hydroxy-N-2-fluorenylacetamide). Although GSK1322322 had antibacterial activity, it was only active against selected bacterial strains (Naderer et al, 2013A).…”

Section: Discussionmentioning

confidence: 99%

Investigation of Metabolism and Disposition of GSK1322322, a Peptidase Deformylase Inhibitor, in Healthy Humans Using the Entero-Test for Biliary Sampling

et al. 2014

View full text Add to dashboard Cite

“…Several workers (8)(9)(10)(11) have demonstrated the reduction of N-OH-AAF by mammalian tissue homogenate or a 10 000 g supernatant fraction. A role of intestinal bacteria in the reduction of N-OH-AAF was also demonstrated by Weisburger et al (6)(7)(8). Gutmann and Erickson (12) reported that N-OH-AAF was reduced to AAF by mammalian liver cytosol.…”

mentioning

confidence: 77%

“…N-hydroxylation of AAF is an essential first step in the metabolic activation of the carcinogen (2)(3)(4). The N-hydroxylated product, N-hydroxy-2-acetylaminofluorene (N-OH-AAF), is further metabolized by such reactions as hydroxylation (5), reduction (6)(7)(8)(9)(10)(11)(12)(13)(14), deacetylation (9)(10)(11)15), conjugation (1) and isomerization (12). Among these reactions, the reduction of N-OH-AAF to the parent compound AAF is a detoxification step of the hydroxamic acid.…”

mentioning

confidence: 99%

Pseudoenzymatic reduction of N-hydroxy-2-acetylaminofluorene to 2-acetylaminofluorene mediated by cytochrome P450

et al. 1999

View full text Add to dashboard Cite

N-hydroxy-2-acetylaminofluorene (N-OH-AAF) was reduced to 2-acetylaminofluorene by rat liver microsomes in the presence of both NAD(P)H and FAD under anaerobic conditions. The microsomal reduction proceeds as if it were an enzymatic reaction. However, when the microsomes were boiled, the activity was not abolished, but was enhanced. The activity was also observed with cytochrome P450 2B1 alone, without NADPH-cytochrome P450 reductase, in the presence of these cofactors. Hematin also exhibited a significant reducing activity in the presence of both a reduced pyridine nucleotide and FAD. The activities of microsomes, cytochrome P450 2B1 and hematin were also observed upon the addition of photochemically reduced FAD instead of both NAD(P)H and FAD. The microsomal reduction of N-OH-AAF appears to be a non-enzymatic reaction by the reduced flavin, catalyzed by the heme group of cytochrome P450.

show abstract

Metabolism of the carcinogen N-hydroxy-N-2-fluorenylacetamide in germ-free rats

Cited by 63 publications

References 14 publications

Silymarin, a naturally occurring polyphenolic antioxidant flavonoid, inhibits azoxymethane‐induced colon carcinogenesis in male F344 rats

Silymarin, a naturally occurring polyphenolic antioxidant flavonoid, inhibits azoxymethane‐induced colon carcinogenesis in male F344 rats

Investigation of Metabolism and Disposition of GSK1322322, a Peptidase Deformylase Inhibitor, in Healthy Humans Using the Entero-Test for Biliary Sampling

Pseudoenzymatic reduction of N-hydroxy-2-acetylaminofluorene to 2-acetylaminofluorene mediated by cytochrome P450

Contact Info

Product

Resources

About