Safingol toxicology after oral administration to TRAMP mice: demonstration of safingol uptake and metabolism by N-acylation and N-methylation.
Safingol [(2S,3S)-2-amino-1,3-octadecanediol] is an unnatural l-threo-stereoisomer of sphinganine that is cytotoxic for cancer cells in culture and is being tested in phase 1 human clinical trials. To determine if safingol can be absorbed orally and if it affects prostate cancer in a mouse strain used in prostate cancer studies, safingol was fed to TRAMP (transgenic adenocarcinoma of mouse prostate) mice for 2 weeks at 0.0125% to 0.1% w/w of the diet. Analysis of safingol and safingol metabolites in blood and tissues by liquid chromatography electrospray ionization tandem mass spectrometry revealed uptake in tissue and extensive conversion of safingol to N-acyl species (comparable to natural "ceramides") and mono-, di-, and tri-N-methyl metabolites that have not been observed previously. Safingol caused significant hepatotoxicity at all dosages, as reflected in elevated liver alanine aminotransferase, and at the highest dose (0.1 %) caused changes in liver histology (appearance of autophagosomal vacuoles) and renal toxicity (based on elevation of blood urea nitrogen) and decreases in packed blood cell volume and body weight. Safingol did not inhibit the prostate pre-neoplastic lesion (prostate intraepithelial neoplasia) in TRAMP mice; however, additional studies at lower dosages for longer time were not pursued due to host toxicity. Safingol and its N-methyl metabolites were cytotoxic to both a human prostate cell line (DU145) and mouse BALB 3T3 cells; therefore, the host and potential antitumor toxicity may be due to multiple molecular species of safingol.
Morales
Pablo R
PR
Division of Animal Resources, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Dillehay
Dirck L
DL
Moody
Steven J
SJ
Pallas
David C
DC
Pruett
Sarah
S
Allgood
Jeremy C
JC
Symolon
Holly
H
Merrill
Alfred H
AH
D000215:Acylation; D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use / Q000633:toxicity*; D041702:BALB 3T3 Cells; D001711:Biotransformation; D001835:Body Weight / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury; D002851:Chromatography, High Pressure Liquid; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006400:Hematocrit; D006801:Humans; D007674:Kidney Diseases / Q000139:chemically induced; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008107:Liver Diseases / Q000473:pathology; D008297:Male; D008745:Methylation; D051379:Mice; D008822:Mice, Transgenic; D019048:Prostatic Intraepithelial Neoplasia / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D021241:Spectrometry, Mass, Electrospray Ionization; D013110:Sphingosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use / Q000633:toxicity; D014018:Tissue Distribution
D000970:Antineoplastic Agents; D013110:Sphingosine; C005682:safingol