Mutagenicity testing of steroids obtained from bile acids and cholesterol

McKillop, Christine A.; Owen, Robert W.; Bilton, Rodney F.; Haslam, Elizabeth A.

doi:10.1093/carcin/4.9.1179

Cited by 20 publications

(6 citation statements)

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“…The genetic toxicity studies in bacteria and cts on male rodents reported here were negative, with the exception of an equivocal response in the peripheral blood micronucleus test in the high dose female mice exposed to androstenedione for 14 weeks. These results are in agreement with other published genetic toxicity test results (McKillop et al, 1983). …”

Section: Discussionsupporting

confidence: 94%

“…Mutagenicity was not seen with androstenedione (500 μg/disc) in a spot test using S. typhimurium strain TA1538, with and without induced rat liver S9 enzymes (McKillop et al, 1983). A more potent androgen, testosterone (500 μg/plate), was negative in S. typhimurium strains TA100, TA1535, and TA1538, with and without rat liver S9 (Ingerowski et al, 1981).…”

Section: Introductionmentioning

confidence: 99%

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Toxicity and carcinogenicity of androstenedione in F344/N rats and B6C3F1 mice

Blystone

Elmore

Witt

et al. 2011

Food and Chemical Toxicology

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Androstenedione was marketed as a dietary supplement to increase muscle mass during training. Due to concern over long-term use, the NTP evaluated the subchronic and chronic toxicity and carcinogenicity of androstenedione in male and female F344/N rats and B6C3F1 mice. In subchronic studies, dose limiting effects were not observed. A chronic (two-year) exposure by gavage at 10, 20, or 50 mg/kg in rats and male mice, and 2, 10, or 50 mg/kg in female mice (50 mg/kg, maximum feasible dose) was conducted. Increased incidences of lung alveolar/bronchiolar adenoma and carcinoma occurred in the 20 mg/kg male rats and increases in mononuclear cell leukemia occurred in the 20 and 50 mg/kg female rats, which may have been related to androstenedione administration. In male and female mice, androstenedione was carcinogenic based upon a significant increase in hepatocellular tumors. A marginal increase in pancreatic islet cell adenomas in male (50 mg/kg) and female (2, 10, 50 mg/kg) mice was considered to be related to androstenedione administration. Interestingly, incidences of male rat Leydig cell adenomas and female rat mammary gland fibroadenomas decreased. In conclusion, androstenedione was determined to be carcinogenic in male and female mice, and may have been carcinogenic in rats.

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Section: Discussionsupporting

confidence: 94%

Section: Introductionmentioning

confidence: 99%

Toxicity and carcinogenicity of androstenedione in F344/N rats and B6C3F1 mice

Blystone

Elmore

Witt

et al. 2011

Food and Chemical Toxicology

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“…Several bacterial studies have revealed the mutagenic effects of BA and their metabolites. Through single‐gel electrophoresis assays, Ames tests, fluctuation assays, and reversion assays in various Salmonella strains, research groups have identified the formation of DSBs, single‐strand DNA breaks, abasic sites, frameshift mutations, base‐pair substitutions, and point mutations in response to bile‐salt exposure . Results have shown that frameshift mutations (−1) were a result of the adaptive SOS response to the stressor BA, and point mutations were largely comprised of nucleotide substitutions (GC to AT transitions), suggesting that exposure to BA salts can result in oxidative DNA damage …”

Section: Dna Damagementioning

confidence: 99%

Obesity and cancer: A mechanistic overview of metabolic changes in obesity that impact genetic instability

Kompella

Vásquez

2019

Molecular Carcinogenesis

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Obesity, defined as a state of positive energy balance with a body mass index exceeding 30 kg/m2 in adults and 95th percentile in children, is an increasing global concern. Approximately one‐third of the world's population is overweight or obese, and in the United States alone, obesity affects one in six children. Meta‐analysis studies suggest that obesity increases the likelihood of developing several types of cancer, and with poorer outcomes, especially in children. The contribution of obesity to cancer risk requires a better understanding of the association between obesity‐induced metabolic changes and its impact on genomic instability, which is a major driving force of tumorigenesis. In this review, we discuss how molecular changes during adipose tissue dysregulation can result in oxidative stress and subsequent DNA damage. This represents one of the many critical steps connecting obesity and cancer since oxidative DNA lesions can result in cancer‐associated genetic instability. In addition, the by‐products of the oxidative degradation of lipids (e.g., malondialdehyde, 4‐hydroxynonenal, and acrolein), and gut microbiota‐mediated secondary bile acid metabolites (e.g., deoxycholic acid and lithocholic acid), can function as genotoxic agents and tumor promoters. We also discuss how obesity can impact DNA repair efficiency, potentially contributing to cancer initiation and progression. Finally, we outline obesity‐related epigenetic changes and identify the gaps in knowledge to be addressed for the development of better therapeutic strategies for the prevention and treatment of obesity‐related cancers.

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“…However, although the epidemiological evidence favors a role for the NDC, unsaturated bile acids of the type expected have yet to be isolated and identified in feces. Furthermore, McKillop and colleagues (4) have shown that a range of unsaturated steroids derived from bile acids and cholesterol are not mutagenic in the Ames salmonella mutagenicity assay.…”

Section: Introductionmentioning

confidence: 99%

Fecal steroids and colorectal cancer

Owen

Dodo

Thompson

et al. 1987

Nutrition and Cancer

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The fecal steroid profiles of healthy subjects were compared with those of colorectal cancer (CRC) patients. The multicomponent profiles did not differ qualitatively in that CRC patients, like control subjects, had similar fecal steroids. The major bile acids detected in fecal extracts were lithocholic acid (LCA) and deoxycholic acid (DCA). The major sterol of animal origin was cholesterol and its bacterial metabolite coprostanol, whereas the major plant sterols were beta-sitosterol, stigmasterol, campesterol, and their corresponding bacterial metabolites. CRC patients excreted higher amounts of total major bile acids (LCA and DCA) than did the control group, but this difference was not significant. However, the LCA-to-DCA ratio was much higher in the CRC group [(1.43, p less than 0.01) compared with the control group (0.72)]. The control group excreted significantly higher amounts of total neutral sterols (p less than 0.001), sterols of animal origin (p less than 0.001), and plant sterols (p less than 0.001) compared with the CRC group; the plant sterols represented a much lower proportion of excreted total neutral sterols in the CRC group (p greater than 0.001) compared with the control group. We propose the following hypotheses. The LCA-to-DCA ratio may be an important discriminant market for CRC susceptibility. The fecal LCA-to-DCA ratio may depend on the differential hepatic synthesis of their respective precursors chenodeoxycholic acid (CDCA) and cholic acid. Hepatic synthesis of CDCA may be increased by more efficient conservation of dietary cholesterol because it has been shown that cholesterol of exogenous origin is the main precursor of this bile acid.(ABSTRACT TRUNCATED AT 250 WORDS)

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Mutagenicity testing of steroids obtained from bile acids and cholesterol

Cited by 20 publications

References 0 publications

Toxicity and carcinogenicity of androstenedione in F344/N rats and B6C3F1 mice

Toxicity and carcinogenicity of androstenedione in F344/N rats and B6C3F1 mice

Obesity and cancer: A mechanistic overview of metabolic changes in obesity that impact genetic instability

Fecal steroids and colorectal cancer

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