title: Inhibition of polyamine oxidase in rats improves the sensitivity of urinary polyamines as markers for cell death.
abstract: In this study we investigated polyamine metabolism during inhibition of two polyamine-catabolizing enzymes. This was performed by treating rats with aminoguanidine [an inhibitor of Cu-dependent amine oxidase (CuAO)], NN'-bis(buta-2,3-dienyl)butane-1,4-diamine [MDL 72527, an inhibitor of FAD-dependent polyamine oxidase (PAO)], tetrachloromethane (hepatotoxic agent) and combinations of these compounds. Emphasis was laid on the origin and possible clinical usefulness of two polyamine metabolites: acetylisoputreanine-gamma-lactam and N1N12-diacetylspermine. Acetylisoputreanine-gamma-lactam is a normal constituent of human and rat urine. Treatment of rats with aminoguanidine led to undetectable urinary levels of acetylisoputreanine-gamma-lactam, whereas MDL 72527 treatment resulted in a 12-fold increase. Under normal conditions this compound represents a minor CuAO catabolite of N1-acetylspermidine, but may become of more importance under CuAO-induced conditions. N1N12-diacetylspermine was undetectable in urine samples from non-pregnant adults and rats, but became detectable after treating rats with MDL 72527. Additional tetrachloromethane poisoning resulted in a 35-fold increase of N1N12-diacetylspermine in urine and its appearance in liver. Hence urinary excretion of N1N12-diacetylspermine during PAO inhibition may serve as a sensitive marker for cell death. This was confirmed by myeloid-leukaemia-bearing rats treated with MDL 72527, which also excreted N1N12-diacetylspermine in urine in relatively high amounts from at least day 14 until spontaneous death.
authors.affiliation: Central Laboratory for Clinical Chemistry, University Hospital Groningen, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Hessels
authors.forename: H
authors.initials: H
authors.lastname: Ferwerda
authors.forename: A W
authors.initials: AW
authors.lastname: Kingma
authors.forename: F A
authors.initials: FA
authors.lastname: Muskiet
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor; D002251:Carbon Tetrachloride / Q000494:pharmacology; D002470:Cell Survival; D005260:Female; D006801:Humans; D007951:Leukemia, Myeloid / Q000175:diagnosis* / Q000188:drug therapy; D008099:Liver / Q000032:analysis; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000037:antagonists & inhibitors*; D011073:Polyamines / Q000652:urine*; D011700:Putrescine / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D000097667:Polyamine Oxidase
chemical_list: D014408:Biomarkers, Tumor; D002251:Carbon Tetrachloride; D000587:Oxidoreductases Acting on CH-NH Group Donors; D011073:Polyamines; D011700:Putrescine; D000097667:Polyamine Oxidase; C044445:MDL 72527