Zinc mesoporphyrin represses induced hepatic 5-aminolevulinic acid synthase and reduces heme oxygenase activity in a mouse model of acute hepatic porphyria.
Zinc mesoporphyrin (ZnMP) is a potent inhibitor of heme oxygenase (HO) and represses 5-aminolevulinic acid synthase (ALAS). These properties make it a potential candidate for treatment of inducible acute hepatic porphyrias, diseases characterized by neurovisceral symptoms, and massive ALAS induction. Effects of intraperitoneal ZnMP (2.5-10 micromol/kg/d) and heme arginate (3-6 mg/kg/d) on plasma levels of 5-aminolevulinic acid (ALA), on messenger RNA (mRNA), and activity of hepatic ALAS and HO were studied in porphobilinogen deaminase-deficient mice treated with phenobarbital (100 mg/kg/d) to induce ALAS. ZnMP (5 micromol/kg/d) led to a significant reduction of plasma ALA levels to 31% of controls (P < .01) by lowering the activity of hepatic mitochondrial and cytosolic ALAS to 29% and 25% of controls, respectively (P < .03). ZnMP decreased the mRNA levels of hepatic ALAS to 53% (P < .03) of controls and this repression was more pronounced than that achieved with heme arginate. In contrast to heme arginate, ZnMP led to a significant reduction of HO activity. We conclude that the combined effect of ZnMP on highly induced ALAS and on HO may be of potential benefit for human acute hepatic porphyrias and therefore merits further in vivo investigations addressing questions raised by this study.
Schuurmans
M M
MM
Division of Pharmacology/Neurobiology, Biozentrum, University of Basel, Switzerland.
Hoffmann
F
F
Lindberg
R L
RL
Meyer
U A
UA
D000624:5-Aminolevulinate Synthetase / Q000037:antagonists & inhibitors* / Q000235:genetics; D000208:Acute Disease; D000622:Aminolevulinic Acid / Q000097:blood; D000818:Animals; D001120:Arginine / Q000494:pharmacology; D003600:Cytosol / Q000201:enzymology; D004338:Drug Combinations; D005260:Female; D006418:Heme / Q000378:metabolism / Q000494:pharmacology; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007274:Injections, Intraperitoneal; D008099:Liver / Q000201:enzymology* / Q000378:metabolism; D008665:Metalloporphyrins / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008930:Mitochondria, Liver / Q000201:enzymology; D010634:Phenobarbital / Q000494:pharmacology; D017118:Porphyria, Acute Intermittent; D017094:Porphyrias, Hepatic / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D012016:Reference Values
D004338:Drug Combinations; D008665:Metalloporphyrins; D012333:RNA, Messenger; D006418:Heme; D000622:Aminolevulinic Acid; D001120:Arginine; C058069:zinc mesoporphyrin; D006419:Heme Oxygenase (Decyclizing); D000624:5-Aminolevulinate Synthetase; C048849:heme arginate; D010634:Phenobarbital