Arylacetamide Deacetylase Enzyme: Presence and Interindividual Variability in Human Lungs

Abstract

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 (n 5 25) using phenacetin as a selective substrate. The kinetic parameters K m and V max 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 K m 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 (*P < 0.05) and protein (*P < 0.05) levels. Moreover, the average values of AADAC activity in smokers was significantly higher than in nonsmoker subjects (*P < 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.

Effect of Genetic Variations in Drug-Metabolizing Enzymes and Drug Transporters on the Pharmacokinetics of Rifamycins: A Systematic Review

“… 41 , 44 Furthermore, Gabriele et al discovered the presence and inter-individual variation of AADAC in the human lung. 64 These findings suggest the important role of AADAC pharmacogenetics in tuberculosis drug therapy.…”

Regulation of Human Hydrolases and Its Implications in Pharmacokinetics and Pharmacodynamics

“…Interestingly, Fukami et al conducted kinetic and inhibition studies in human liver microsomes and identified AADAC as the enzyme that metabolizes ketoconazole to DAK (Fukami et al, 2016). AADAC is expressed in the liver and small intestine and is also present in the lungs at a lower level (Figure 2) (Gabriele et al, 2019;Fukami et al, 2022). Overexpression of AADAC in ovarian cancer tissues has been found to promote therapeutic activity of cisplatin and imatinib against ovarian cancer cells (Wang et al, 2022).…”

“…Gabriele and colleagues not only demonstrated the presence of AADAC protein in the lung through immunoblot analysis but also observed high interindividual variability in both AADAC mRNA levels and the enzymatic activity in hydrolyzing phenacetin, a known AADAC substrate (Gabriele et al, 2019). The impact of SNPs on the AADAC's activity hydrolyzing eslicarbazepine acetate was studied in small intestine and liver microsomes (Hirosawa et al, 2021), where samples with the SNPs R248S or X400Q showed lower activity than the wild type (5% or 21%, respectively), and those with V172I showed higher activity than the wild type (174%).…”