The toxicity and pharmacokinetics of dihydrosanguinarine in rat: a pilot study.
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).
Vrublova
Eva
E
Department of Medical Chemistry and Biochemistry, Faculty of Medicine and Dentistry, Palacky University, Hnevotinska 3, 775 15 Olomouc, Czech Republic.
Vostalova
Jitka
J
Vecera
Rostislav
R
Klejdus
Borivoj
B
Stejskal
David
D
Kosina
Pavel
P
Zdarilova
Adela
A
Svobodova
Alena
A
Lichnovsky
Vaclav
V
Anzenbacher
Pavel
P
Dvorak
Zdenek
Z
Vicar
Jaroslav
J
Simanek
Vilim
V
Ulrichova
Jitka
J
D000821:Animal Feed; D000818:Animals; D019540:Area Under Curve; D053119:Benzophenanthridines / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity*; D001774:Blood Chemical Analysis; D020552:Comet Assay; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects; D018736:DNA Adducts; D004249:DNA Damage / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D007082:Ileum / Q000187:drug effects / Q000473:pathology; D007546:Isoquinolines / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity*; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008297:Male; D009152:Mutagenicity Tests; D009929:Organ Size / Q000187:drug effects; D009928:Organ Specificity; D018384:Oxidative Stress / Q000187:drug effects*; D010865:Pilot Projects; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D014018:Tissue Distribution
D053119:Benzophenanthridines; D018736:DNA Adducts; D007546:Isoquinolines; C501843:dihydrosanguinarine; D003577:Cytochrome P-450 Enzyme System