The toxicity and pharmacokinetics of dihydrosanguinarine in rat: A pilot study

• Published in: Food and chemical toxicology 2008-07, Vol.46 (7), p.2546-2553
• Main Authors: Vrublova, Eva, Vostalova, Jitka, Vecera, Rostislav, Klejdus, Borivoj, Stejskal, David, Kosina, Pavel, Zdarilova, Adela, Svobodova, Alena, Lichnovsky, Vaclav, Anzenbacher, Pavel, Dvorak, Zdenek, Vicar, Jaroslav, Simanek, Vilim, Ulrichova, Jitka
• Format: Article
• Language: English
• Subjects: Animal Feed; animal models; Animals; Area Under Curve; Benzo[ c]phenanthridine alkaloid; Benzophenanthridines - blood; Benzophenanthridines - pharmacokinetics; Benzophenanthridines - toxicity; Biological and medical sciences; blood; Blood Chemical Analysis; body weight; Comet Assay; cytochrome P-450; Cytochrome P-450 Enzyme System - drug effects; cytotoxicity; Dietary toxicity; Dihydrosanguinarine; Disposition; DNA; DNA Adducts; DNA damage; DNA Damage - drug effects; dose response; Dose-Response Relationship, Drug; feed additives; genotoxicity; gingiva; heart; hepatocytes; hepatotoxicity; ileum; Ileum - drug effects; Ileum - pathology; Isoquinolines - blood; Isoquinolines - pharmacokinetics; Isoquinolines - toxicity; kidneys; liver; Liver - drug effects; Liver - pathology; lymphocytes; Male; Medical sciences; Metabolism; metabolites; Mutagenicity Tests; Organ Size - drug effects; Organ Specificity; oxidative stress; Oxidative Stress - drug effects; pharmacokinetics; Pilot Projects; Random Allocation; Rats; Rats, Wistar; Sanguinarine; Time Factors; Tissue Distribution; tissue weight; tongue; Toxicology
• ISSN: 0278-6915; 1873-6351
• DOI: 10.1016/j.fct.2008.04.013

The quaternary benzo[ c]phenanthridine alkaloid sanguinarine (SG) is the main component of Sangrovit ®, a natural livestock feed additive. Dihydrosanguinarine (DHSG) has recently been identified as a SG metabolite in rat. The conversion of SG to DHSG is a likely elimination pathway of SG in mammals. This study was conducted to evaluate the toxicity of DHSG in male Wistar rats at concentrations of 100 and 500 ppm DHSG in feed for 90 days (average doses of 14 and 58 mg DHSG/kg body weight/day). No significant alterations in body or organ weights, macroscopic details of organs, histopathology of liver, ileum, kidneys, tongue, heart or gingiva, clinical chemistry or hematology markers in blood in the DHSG-treated animals were found compared to controls. No lymphocyte DNA damage by Comet assay, formation of DNA adducts in liver by 32P-postlabeling, modulation of cytochrome P450 1A1/2 or changes in oxidative stress parameters were found. Thus, repeated dosing of DHSG for 90 days at up to 500 ppm in the diet (i.e. approximately 58 mg/kg/day) showed no evidence of toxicity in contrast to results published in the literature. In parallel, DHSG pharmacokinetics was studied in rat after oral doses 9.1 or 91 mg/kg body weight. The results showed that DHSG undergoes enterohepatic cycling with maximum concentration in plasma at the first or second hour following application. DHSG is cleared from the body relatively quickly (its plasma levels drop to zero after 12 or 18 h, respectively).