Kastelova A, Yanev S
Laboratory of Drug Toxicology, Institute of Physiology, Bulgarian Academy of Sciences, Sofia, Bulgaria.
Methods Find Exp Clin Pharmacol. 2002 May;24(4):189-94. doi: 10.1358/mf.2002.24.4.678449.
The in vitro effect of propranolol (10(-3) M and 10(-4) M), a nonselective and extensively metabolized beta-adrenergic blocking agent, on rat liver drug metabolism in native and induced (with phenobarbital and beta-naphthoflavone [beta-NF]) microsomes was studied. The type of inhibition and the inhibitory constants of some cytochrome P450-dependent microsomal enzyme reactions (hexobarbital oxidation [HBO], ethylmorphine-N-demethylation [EMND], aniline hydroxylation [AH], ethoxycoumarin-O-deethylation [ECOD], ethoxyresorufin-O-dealkylation [EROD] and penthoxyresorufin-O-dealkylation [PROD]) were estimated. The results showed that propranolol competitively inhibited AH activity in native microsomes. The type of inhibition was changed from competitive to noncompetitive in all other enzyme activities studied. This inhibition was more pronounced after phenobarbital induction in PROD (Ki = 0.11 +/- 0.01 mM), ECOD (Ki = 0.40 +/- 0.09 mM) and EMND (Ki = 0.59 +/- 0.1 mM), and after beta-NF induction in AH (Ki = 0.28 +/- 0.05 mM) and in HBO (Ki = 0.35 +/- 0.1 mM) in native microsomes. It was assumed that the noncompetitive type of inhibition is due to the covalent binding of reactive metabolites derived from propranolol to hepatic microsomal proteins. The competitive type of inhibition of AH suggested a common P450 isoenzyme in the metabolism of propranolol and aniline. Thus, in this study, propranolol has been found to be not only a selective inhibitor of CYP2D6 isoenzyme-dependent reactions, but also a nonspecific inhibitor of other cytochrome P450 isoenzymes.
研究了非选择性且广泛代谢的β-肾上腺素能阻滞剂普萘洛尔（10⁻³ M和10⁻⁴ M）对大鼠肝脏天然微粒体和诱导微粒体（用苯巴比妥和β-萘黄酮[β-NF]诱导）药物代谢的体外作用。估计了一些细胞色素P450依赖性微粒体酶反应（己巴比妥氧化[HBO]、N-脱乙基吗啡[EMND]、苯胺羟化[AH]、乙氧香豆素-O-脱乙基[ECOD]、乙氧试卤灵-O-脱烷基化[EROD]和戊氧试卤灵-O-脱烷基化[PROD]）的抑制类型和抑制常数。结果表明，普萘洛尔竞争性抑制天然微粒体中的AH活性。在所研究的所有其他酶活性中，抑制类型从竞争性变为非竞争性。在天然微粒体中，苯巴比妥诱导后，PROD（Ki = 0.11±0.01 mM）、ECOD（Ki = 0.40±0.09 mM）和EMND（Ki = 0.59±0.1 mM）的这种抑制作用更明显；β-NF诱导后，AH（Ki = 0.28±0.05 mM）和HBO（Ki = 0.35±0.1 mM）的抑制作用更明显。据推测，非竞争性抑制类型是由于普萘洛尔衍生的活性代谢产物与肝微粒体蛋白的共价结合。AH的竞争性抑制类型表明普萘洛尔和苯胺代谢中存在共同的P450同工酶。因此，在本研究中，发现普萘洛尔不仅是CYP2D6同工酶依赖性反应的选择性抑制剂，也是其他细胞色素P450同工酶的非特异性抑制剂。
