A Comparison of the Expression and Metabolizing Activities of Phase I and II Enzymes in Freshly Isolated Human Lung Parenchymal Cells and Cryopreserved Human Hepatocytes

Abstract

ABSTRACT:The pulmonary and hepatic expression and catalytic activities of phase I and II drug-metabolizing enzymes were compared using human lung and liver tissue, and lung parenchymal cells (LPCs) and cryopreserved hepatocytes. Cytochrome P450 gene expression was generally lower in lung than in liver and CYP3A4 expression in lung was negligible. Esterase gene expression was similar in lung and liver. Expression of all sulfotransferase isoforms in lung was similar to or higher than that in liver. Lung tissue expressed low levels of UGT. However, the expression of UGT2A1 in lung was higher than that in liver. There was a range of catalytic activities in LPCs, including cytochrome P450, esterase, and sulfation pathways. Phase I activities were generally less than 10% of those determined in hepatocytes. Rates of ester hydrolysis and sulfation in LPCs were similar to those in hepatocytes. When measurable, glucuronidation in LPCs was present at very low levels, reflecting the gene expression data. The metabolism of salbutamol, formoterol, and budesonide was also investigated. Production of salbutamol-4-O-sulfate and budesonide oleate was observed in LPCs from at least two of three donor preparations studied. Formoterol sulfate and low levels of formoterol glucuronide were detected in one of three donors. In general, drug-metabolizing capability of LPCs is low compared with liver, although some evidence for substantial sulfation and deesterification capacity was observed. Therefore, these data support the use of this cell-based system for the investigation of key routes of xenobiotic metabolism in human lung parenchyma.

Pulmonary Metabolism of Resveratrol: In Vitro and In Vivo Evidence

“…UGT expression and activity have been reported in the upper respiratory tract but not in lungs in humans (Zheng et al, 2002), which becomes important for inhaled compounds. Other studies have shown low or no UGT expression in normal human lung tissue (Zheng et al, 2002;Somers et al, 2007;Nakamura et al, 2008). In the present study, the absence of R3G formation in human lung fraction is consistent with low or absent expression of UGT isoforms in normal human lung tissue (Nakamura et al, 2008) responsible for RES glucuronidation (Brill et al, 2006).…”

Detoxication of Benzo[a]pyrene-7,8-dione by Sulfotransferases (SULTs) in Human Lung Cells

“…It is possible that inhibition to SULT1E1 by B[a]P-7,8-catechol and other PAH catechols may increase the risk factor for estrogen-dependent genotoxicity. (34,44) and suggests that is reasonable to infer from our cell-based study that both enzymes will play a significant role in the detoxication of B[a]P-7,8-dione.…”

“Target-Site” Drug Metabolism and Transport

“…SULT pulmonary expression has similarly been reported, with low expression overall; SULT1E1 levels in the lung were the highest, followed by SULT1A1, 1A3, 1B1, and 2A1 (Riches et al, 2009). Somers et al (2007) reported robust expression of several SULT isozymes in human lung parenchyma relative to human liver. Pharmacogenetic variability in XMEs can impact their role in the overall disposition of drugs and xenobiotics, and may predict the clinical outcome.…”

“…Nakamura et al (2008) detected UGT2B4 and 2B7 in normal human lung samples, whereas UGT1A1 and 1A3 were additionally reported in human lung adenocarcinoma A549 cell lines . In another study, relatively high UGT1A6 and 2A1 were reported in human lung parenchyma, comparable to human liver expression (Somers et al, 2007). A recent study evaluated UGT2B expression in the upper respiratory tract, and reported low expression of various UGT2B isozymes (2B4, 2B7, 2B10, 2B11, 2B15, and 2B17) in the human lung (Jones and Lazarus, 2014).…”

“…P450 expression in various pulmonary cell lines representing the complex heterogenous cell layers of the lung has been reported, and variable P450 isozyme levels are thought to be expressed across the pulmonary cell layers (Gundert-Remy et al, 2014). Thus, Somers et al (2007) reported modest human lung parenchymal levels of CYP1A1, 2J2, and 2A5, but lower expression levels compared with the liver. Numerous studies have shown modest expression of CYP1A1 in the bronchus and lung, with highly induced levels of the enzyme in smokers (Anttila et al, 2011).…”