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, d iseases characterized by neurovisceral symptoms, and massive ALAS induction . Effects of intraperitoneal ZnMP (2.5-10 mu mol/kg/d) and heme arginate (3 -6 mg/kg/d) on plasma levels of 5-aminolevulinic acid (ALA), on messenger R NA (mRNA), and activity of hepatic ALAS and HO were studied in porphobilino gen deaminase-deficient mice treated with phenobarbital (100 mg/kg/d) to in duce ALAS. ZnMP (5 mu mol/kg/d) led to a significant reduction of plasma AL A levels to 31% of controls (P < .01) by lowering the activity of hepatic m itochondrial 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 h eme arginate, In contrast to heme arginate, ZnMP led to a significant reduc tion 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.