Received for publication March 26, 2007.
Revised June 11, 2007.
Accepted for publication July 9, 2007.

A comparison of the expression and metabolising activities of Phase I and II enzymes in freshly isolated human lung parenchymal cells and cryopreserved human hepatocytes

Abstract

The pulmonary and hepatic expression and catalytic activities of phase I and II drug metabolising enzymes were compared using human lung and liver tissue, and lung parenchymal cells (LPCs) and cryopreserved hepatocytes. Cytochrome P450 (CYP) 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 SULT isoforms was similar or higher in lung than 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 CYP, esterase and sulfation pathways. Phase I activities were generally less than 10% of those determined in hepatocytes. Rates of ester hydrolysis and sulfation in LPC's 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 were also investigated. Production of salbutamol-4-O-sulfate and budesonide oleate was observed in LPCs from at least two out of three donor preparations studied. Formoterol sulfate and low levels of fomoterol glucuronide were detected in one out of three donors. In general, drug metabolising capability of LPCs is low compared to liver although some evidence for substantial sulfation and desterification 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.

Key words: CYP expression, cytochrome P450 function, glucuronidation, inhaled drugs, lung cytochrome P450, sulfate conjugation

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