The effect of therapeutic drugs and other pharmacologic agents on activityof porphobilinogen deaminase, the enzyme that is deficient in intermittentacute porphyria

Drugs and toxins precipitate life-threatening acute attacks in patients wit h intermittent acute porphyria. These materials may act by directly inhibit ing enzyme activity, thus further reducing porphobilinogen (PBG) deaminase activity below the ca. 50% level that results from the gene defect. To test this, we studied the effects of drugs that precipitate acute attacks (lead , phenobarbital, griseofulvin, phenytoin, sulfanilamide, sulfisoxazole, 17 alpha-ethinyl estradiol, 5 beta-pregnan-3 alpha-ol-20-one), drugs that are safe (lithium, magnesium, chlorpromazine, promethazine), and those with unc ertain effects (ethyl alcohol, imipramine, diazepam, haloperidol) on activi ty of PEG deaminase in vitro and in vivo. In the in vitro studies, of PEG d eaminase from human erythrocytes from normals and individuals with IAP, onl y lead (greater than or equal to.01 mM) inhibited enzyme activity. Chlorpro mazine (greater than or equal to.01 mM), promethazine (2.01 mM) and imipram ine (1 mM) seemed to increase enzyme activity. In most in vivo experiments, male rats were injected intraperitoneally with test material twice daily f or 3 days and once on day four; and erythrocyte and hepatic PEG deaminase a ctivity was assayed thereafter. Effects on enzyme activity were observed on ly with 17 alpha-ethinyl estradiol (0.05 mu g/kg/day; reduction of 11% in e rythrocyte enzyme [NS], and of 20% in liver enzyme [P=.02]), and imipramine (12.5 mg/kg/day; reduction in erythrocyte enzyme activity of 13% [P<.001]) . Rats given lead acetate in their drinking water (10 mg/ml) for the first 60 days of life, resulting in high blood and liver lead levels, had increas ed erythrocyte PEG deaminase (167% of control; P=.004). Thus, enzyme inhibi tion by lead in vitro was not reflected in a similar in vivo inhibition. Th e only inhibitory effects in vivo, with ethinyl estradiol and imipramine, a ppear to be mild and biologically inconsequential. We conclude that inhibit ion of PEG deaminase activity by materials that precipitate acute attacks i s an unlikely mechanism by which these materials exert their harmful effect s in patients with IAP.