MISCELLANEOUS ANALOG INHIBITIONS 611 



Inhibition of Catechol-0-methyitransferase by Pyrogallol 



This inhibition is of interest because of the bearing it has on the metab- 

 olism of epinephrine and norepinephrine. Bacq (1936) observed that pyro- 

 gallol increases the responses of tissues to sympathetic nerve stimulation and 

 to epinephrine. However, he then attributed this action to the antioxidant 

 properties of pyrogallol. Lembeck and Resch (1960) and Vanov (1962) have 

 recently confirmed this by showing that the pressor response to epineph- 

 rine is prolonged by pyrogallol. The inhibition of the catechol-0-methyl- 

 transferase was reported by Bacq et al. (1959), who believed that this could 

 explain the sensitization of smooth muscles to the catecholamines by pyro- 

 gallol and other phenolic compounds. Axelrod and Laroche (1959) also 

 found a potent inhibition of this enzyme (50% when pyrogallol = epineph- 

 rine = 0.01 niM), which decreases with increasing substrate concentration, 

 indicating a competitive action. Furthermore, about 70% of intravenously 

 injected epinephrine-H^ is metabolized in 10 min in mice, but pretreatment 

 with 100 mg/kg pyrogallol reduces the amount metabolized to 22%. The 

 half-life of norepinephrine in mice is increased from 22 to 42 min by 10 mg 

 pyrogallol, while at the same time 0-methylation is inhibited 99%, indi- 

 cating other pathways for norepinephrine metabolism (Udenfriend et al., 

 1959). Probably the monoamine oxidase pathway is also important. The 

 administration of pyrogallol to rats does not by itself increase brain nor- 

 epinephrine levels, but in conjunction with iproniazid (which inhibits mo- 

 noamine oxidase) it does, in this case the two major degradative pathways 

 being blocked (Jaattela and Paasonen, 1961). This is a good example of 

 the action of two inhibitors on a divergent multienzyme system and, in 

 addition, has interesting possibilities for clinical application. 



Repeated administration of pyrogallol causes a rise in the blood pressure 

 but this is soon followed by a loss of response or tachyphylaxis (Wylie et 

 al., 1960). The rate of urinary excretion of 0-methylated derivatives of the 

 catecholamines is briefly decreased by pyrogallol, but if the administration 

 is continued the rate returns to normal (Nukada et al., 1962). Long-term 

 treatment with pyrogallol leads to an increase in 0-methyltransferase and 

 monoamine oxidase in the liver of rats, so it may well be that these enzymes 

 are adaptively altered. The urinary excretion changes of the catecholamines 

 and their 0-methylated products are shown in Fig. 2-23. 



The kinetics of the in vivo inhibition have been studied by Crout (1961). 

 Inhibition of 0-methyltransferase occurs very rapidly in liver, heart, and 

 brain even when the pyrogallol is injected intraperitoneally, and by 30 min 

 has developed appreciably. The inhibition of the enzyme obtained from rat 

 tissues, however, is only partly competitive (actually the curves appear to 

 indicate pure noncompetitive inhibition) despite the fact that pyrogallol 

 is a substrate for the enzyme. The K, of 0.008 vs\M for pyrogallol indicates 

 the high potency of the inhibition (^,„ for norepinephrine is 0.3 vaM). Fur- 



