The fate of 4-hydroxycarbazole metabolite: metabolism and carcinogenicity assessment of a β-adrenergic receptor modulator containing carbazole structure
| Autor: | Chad E. Hadden, Robert J. Barbuch, Ron Lantz, August Wilke, Tao Ji, Minxia M. He, Kristina M. Campanale |
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| Rok vydání: | 2011 |
| Předmět: |
Male
Magnetic Resonance Spectroscopy Carcinogenicity Tests Health Toxicology and Mutagenesis Metabolite Carbazoles Administration Oral Mutagen Pharmacology Biology Toxicology medicine.disease_cause Biochemistry Fluorescence Mass Spectrometry Rats Sprague-Dawley chemistry.chemical_compound In vivo Neoplasms Receptors Adrenergic beta medicine Animals Carcinogen General Medicine Metabolism Survival Analysis In vitro chemistry Carcinogens Female Glucuronide Metabolic Networks and Pathways Conjugate Chromatography Liquid Mutagens |
| Zdroj: | Xenobiotica; the fate of foreign compounds in biological systems. 41(12) |
| ISSN: | 1366-5928 |
| Popis: | LY377604 has a potential to form 4-hydroxycarbazole, which was reported in the literature as a mutagen. This safety concern led to our investigation of the metabolism and carcinogenicity of LY377604. In in vitro studies with LY377604, 4-hydroxycarbazole was detected in the presence of liver microsomes prepared from different species. When incubated with liver slices, only the conjugate of 4-hydroxycarbazole was detected. Subsequent in vivo radio-labelled studies were conducted to characterise the formation of 4-hydroxycarbazole from LY377604. Free 4-hydroxycarbazole was not detected in vivo, but the O-glucuronide conjugate was identified as a minor metabolite in urine samples, representing 0.2% and 0.9% of the radioactive dose in rats and monkeys. The low level of circulating 4-hydroxycarbazole glucuronide conjugate was also detected in plasma. LY377604 was negative in all genetic toxicology assays and was not associated with tumour induction in a 6-month carcinogenicity study using RasH2+/- mouse model. The exposure to free 4-hydroxycarbazole was not measurable after one dose and was about 0.1%-0.2% of the parent exposure at the end of the 6-month study. These data suggested that 4-hydroxycarbazole was formed as a minor metabolite in vivo, but it was primarily conjugated and excreted in urine as the glucuronide conjugate. The absence of tumours in the carcinogenicity study combined with the exposure data suggested that the low level of free 4-hydroxycarbazole did not represent a carcinogenic risk. |
| Databáze: | OpenAIRE |
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