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首页> 外文期刊>Life sciences >The effect of therapeutic drugs and other pharmacologic agents on activity of porphobilinogen deaminase, the enzyme that is deficient in intermittent acute porphyria.
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The effect of therapeutic drugs and other pharmacologic agents on activity of porphobilinogen deaminase, the enzyme that is deficient in intermittent acute porphyria.

机译：治疗药物和其他药物对卟啉胆碱原脱氨酶（间歇性急性卟啉症缺乏的酶）活性的影响。

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Drugs and toxins precipitate life-threatening acute attacks in patients with intermittent acute porphyria. These materials may act by directly inhibiting 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, 17alpha-ethinyl estradiol, 5beta-pregnan-3alpha-ol-20-one), drugs that are safe (lithium, magnesium, chlorpromazine, promethazine), and those with uncertain effects (ethyl alcohol, imipramine, diazepam, haloperidol) on activity of PBG deaminase in vitro and in vivo. In the in vitro studies, of PBG deaminase from human erythrocytes from normals and individuals with IAP, only lead (> or = .01 mM) inhibited enzyme activity. Chlorpromazine (> or = .01 mM), promethazine (> or = .01 mM) and imipramine (1 mM) seemed to increase enzyme activity. In most in vivo experiments, male rats were injected intraperitoneally with test material twice daily for 3 days and once on day four; and erythrocyte and hepatic PBG deaminase activity was assayed thereafter. Effects on enzyme activity were observed only with 17alpha-ethinyl estradiol (0.05 microg/kg/day; reduction of 11% in erythrocyte 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 increased erythrocyte PBG deaminase (167% of control; P=.004). Thus, enzyme inhibition by lead in vitro was not reflected in a similar in vivo inhibition. The only inhibitory effects in vivo, with ethinyl estradiol and imipramine, appear to be mild and biologically inconsequential. We conclude that inhibition of PBG deaminase activity by materials that precipitate acute attacks is an unlikely mechanism by which these materials exert their harmful effects in patients with IAP.
机译：在间歇性急性卟啉症患者中，药物和毒素会引发威胁生命的急性发作。这些物质可以通过直接抑制酶的活性来起作用，从而进一步降低了胆色素原（PBG）脱氨酶的活性，低于ca。基因缺陷导致的水平为50％。为了测试这一点，我们研究了引起急性发作的药物（铅，苯巴比妥，灰黄霉素，苯妥英钠，磺胺，磺胺异恶唑，17α-乙炔雌二醇，5beta-pregnan-3alpha-ol-20-one）的作用，这些药物是安全的（锂，镁，氯丙嗪，异丙嗪）以及在体外和体内对PBG脱氨酶活性影响不确定的化合物（乙醇，丙咪嗪，地西epa，氟哌啶醇）。在体外研究中，正常人和患有IAP的人的红细胞中的PBG脱氨酶只有铅（>或= 0.01 mM）抑制酶活性。氯丙嗪（>或= 0.01 mM），异丙嗪（>或= 0.01 mM）和丙咪嗪（1 mM）似乎增加了酶的活性。在大多数体内实验中，每天两次给雄性大鼠腹膜内注射测试材料，持续3天，第四天一次。然后测定红细胞和肝PBG脱氨酶活性。仅用17α-乙炔基雌二醇（0.05微克/千克/天;红细胞酶[NS]降低11％，肝酶[P = .02]降低20％）和丙咪嗪（12.5）观察到对酶活性的影响。 mg / kg /天;红细胞酶活性降低13％[P <.001]）。在生命的最初60天中，老鼠在饮用水（10 mg / ml）中给予乙酸铅，导致血液和肝脏中的铅含量高，其红细胞PBG脱氨酶增加（对照组的167％; P = .004）。因此，在体外对铅的酶抑制没有反映在类似的体内抑制中。乙炔雌二醇和丙咪嗪在体内的唯一抑制作用似乎是温和的，并且生物学上无关紧要。我们得出的结论是，诱发急性发作的物质抑制PBG脱氨酶活性是一种不太可能的机制，这些物质可通过这些物质对IAP患者发挥有害作用。

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