Inhibitory action of hydralazine on catecholamine-synthesizing enzymes prepared from bovine adrenal medulla.
The direct effect of hydralazine on catecholamine-synthesizing enzymes was investigated. Hydralazine caused a concentration-dependent inhibition of tyrosine hydroxylase (TH) prepared from bovine adrenal medulla, and a more pronounced effect was obtained by incubating the enzyme with the drug prior to the enzyme assay. Kinetic studies showed that hydralazine increased the apparent Km value of the enzyme for tyrosine and cofactor, 6,7-dimethyl-5,6,7,8-tetrahydropterin (DMPH4), without any change in the Vmax. The inhibitory effect of the drug was irreversible, and an excess amount of FeSO4 failed to restore the enzyme activity inhibited by this drug. Furthermore, hydralazine also inhibited the dopamine beta-hydroxylase (DBH) in chromaffin granule membranes. Hydralazine increased the apparent Km value of DBH for ascorbic acid without any change in the Vmax, and it decreased the Vmax of the enzyme for tyramine with no change in the apparent Km value. The observations described here suggest the possibility that hydralazine presumably causes the inhibition of catecholamine-synthesizing enzymes as a result of allosteric alterations in the molecular structures of these enzymes. It thus seems unlikely that the inhibitory action of hydralazine on these enzymes may totally be based on its metal-chelating activity.
Morita
K
K
Houchi
H
H
Nakanishi
A
A
Minakuchi
K
K
Oka
M
M
D000313:Adrenal Medulla / Q000201:enzymology*; D000818:Animals; D002395:Catecholamines / Q000096:biosynthesis; D002417:Cattle; D002614:Chelating Agents / Q000494:pharmacology; D004299:Dopamine beta-Hydroxylase / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D005296:Ferrous Compounds / Q000494:pharmacology; D006830:Hydralazine / Q000494:pharmacology*; D007700:Kinetics; D013696:Temperature; D014446:Tyrosine 3-Monooxygenase / Q000037:antagonists & inhibitors*
D002395:Catecholamines; D002614:Chelating Agents; D005296:Ferrous Compounds; D006830:Hydralazine; C020748:ferrous sulfate; D014446:Tyrosine 3-Monooxygenase; D004299:Dopamine beta-Hydroxylase