Further studies on the ex-vivo effects of procarbazine and monomethylhydrazine on rat semicarbazide-sensitive amine oxidase and monoamine oxidase activities.
Following administration of the anticancer agent, procarbazine, or one of its metabolites, monomethylhydrazine, to rats, activities of monoamine oxidases A and B (MAO A and MAO B) and of semicarbazide-sensitive amine oxidase (SSAO) were measured ex-vivo. Both compounds were found to be potent inhibitors of SSAO in tissue homogenates, exhibiting ID50 values in most tissues of approximately 8 mg kg-1 (procarbazine) and 0.08 mg kg-1 (monomethylhydrazine). Concurrent dose-dependent inhibition of MAO activities did not occur. However, in liver, potentiation of MAO B activity, to 140% of that in controls, was apparent following monomethyl-hydrazine and this effect was independent of the drug dose. Both compounds produced a dose-dependent potentiation of MAO A in brown adipose tissue, the elevation being more pronounced following monomethylhydrazine, with activity rising to 350% of that in control homogenates. In a parallel in-vitro study, monomethylhydrazine was without effect on MAO A in brown adipose tissue homogenates. By perfusing the SSAO substrate, benzylamine, through the isolated mesenteric arterial bed of the rat, it was found that pretreatment of animals with procarbazine or monomethylhydrazine reduced metabolism of this amine by a similar degree as had been determined ex-vivo in blood vessel homogenates. The results presented suggest that these compounds would be suitable for use as selective inhibitors in pharmacological examinations of SSAO function in isolated tissues and organs.
Holt
A
A
Department of Pharmacology, University of Cambridge, UK.
Callingham
B A
BA
D006631:Amine Oxidase (Copper-Containing) / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001596:Benzylamines / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D008995:Monoamine Oxidase / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D009002:Monomethylhydrazine / Q000494:pharmacology*; D011344:Procarbazine / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012663:Semicarbazides / Q000494:pharmacology*; D012680:Sensitivity and Specificity
D000970:Antineoplastic Agents; D001596:Benzylamines; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D008996:Monoamine Oxidase Inhibitors; D012663:Semicarbazides; D011344:Procarbazine; C030796:benzylamine; D006631:Amine Oxidase (Copper-Containing); D008995:Monoamine Oxidase; D009002:Monomethylhydrazine