National Research Council, Institute of Biology and Agricultural Biotechnology (IBBA), Pisa Unit, Research Area of Pisa, Pisa, Italy (M.G., P.G.G., V.L.); Chiesi Farmaceutici S.p.A., Parma, Italy (P.P.); and Division of Thoracic Surgery, Department of Surgical Medical Molecular Pathology and Critical Care, University Hospital of Pisa, Pisa, Italy (M.L., V.A.).
National Research Council, Institute of Biology and Agricultural Biotechnology (IBBA), Pisa Unit, Research Area of Pisa, Pisa, Italy (M.G., P.G.G., V.L.); Chiesi Farmaceutici S.p.A., Parma, Italy (P.P.); and Division of Thoracic Surgery, Department of Surgical Medical Molecular Pathology and Critical Care, University Hospital of Pisa, Pisa, Italy (M.L., V.A.)
Drug Metab Dispos. 2019 Sep;47(9):961-965. doi: 10.1124/dmd.119.087031. Epub 2019 Jun 24.
Human arylacetamide deacetylase (AADAC) is a single microsomal serine esterase involved in the hydrolysis of many acetyl-containing drugs. To date, the presence and activity of the AADAC enzyme in human lungs has been scarcely examined. We investigated its gene and protein expression as well as interindividual variations in AADAC activities in a large number of human lungs ( = 25) using phenacetin as a selective substrate. The kinetic parameters and were determined. Our findings highlighted a high interindividual variability in both AADAC mRNA levels and hydrolysis activities. Furthermore, for the first time we demonstrated the presence of the AADAC protein in various lung samples by means of immunoblot analysis. As a comparison, phenacetin hydrolysis was detected in pooled human liver microsomes. Lung activities were much lower than those found in the liver. However, similar values were found, which suggests that this hydrolysis could be due to the same enzyme. Pulmonary phenacetin hydrolysis proved to be positively correlated with AADAC mRNA (* < 0.05) and protein (* < 0.05) levels. Moreover, the average values of AADAC activity in smokers was significantly higher than in nonsmoker subjects (* < 0.05), and this might have an important role in the administration of some drugs. These findings add more information to our knowledge of pulmonary enzymes and could be particularly useful in the design and preclinical development of inhaled drugs. SIGNIFICANCE STATEMENT: This study investigated the presence and activity of the AADAC enzyme in several human lungs. Our results highlight high interindividual variability in both AADAC gene and protein expression as well as in phenacetin hydrolysis activity. These findings add more information to our knowledge of pulmonary enzymes and could be particularly useful in the design and preclinical development of inhaled drugs.
人芳基乙酰氨基脱乙酰酶（AADAC）是一种单一的微粒体丝氨酸酯酶，参与许多含乙酰基药物的水解。迄今为止，人肺中 AADAC 酶的存在和活性很少被研究。我们使用非那西汀作为选择性底物，研究了大量人肺（= 25）中 AADAC 基因和蛋白表达以及个体间活性的变化。确定了动力学参数和。我们的研究结果强调了 AADAC mRNA 水平和水解活性的个体间高度变异性。此外，我们首次通过免疫印迹分析证明了各种肺样本中 AADAC 蛋白的存在。作为比较，在人肝微粒体中检测到非那西汀水解。肺活性远低于肝脏中发现的活性。然而，发现了相似的值，这表明这种水解可能是由于相同的酶。肺中非那西汀水解被证明与 AADAC mRNA（* < 0.05）和蛋白（* < 0.05）水平呈正相关。此外，吸烟者的 AADAC 活性平均值明显高于非吸烟者（* < 0.05），这在某些药物的给药中可能具有重要作用。这些发现增加了我们对肺酶的认识，并可能在吸入药物的设计和临床前开发中特别有用。意义：本研究研究了几种人肺中 AADAC 酶的存在和活性。我们的结果强调了 AADAC 基因和蛋白表达以及非那西汀水解活性的个体间高度变异性。这些发现增加了我们对肺酶的认识，并可能在吸入药物的设计和临床前开发中特别有用。
