Xenobiotic-Metabolizing Enzymes in Human Lung

Abstract

Human lung is a major target organ for all inhaled drugs, environmental toxicants and carcinogens. Recent hypotheses suggesting a role for environmental toxicants in the pathogenesis of lung diseases, such as lung cancer and chronic obstructive pulmonary disease have stimulated interest in research on the xenobiotic metabolizing capability of the lung. Many of the compounds associated with these diseases require enzymatic activation to exert their deleterious effects on pulmonary cells. Interindividual differences in in situ activation and inactivation of xenobiotics may contribute to the risk of developing of lung diseases associated with these compounds. The major xenobiotic metabolizing enzymes, including both phase I and phase II enzymes, have been detected in animal and human lung tissues. Although the lung cytochrome P450 (CYP) and other xenobiotic metabolizing enzymes share many common features with those present in other tissues such as liver, kidney and gut, there are some distinctive differences. It is evident from the studies carried out to date CYP1A1, 1B1, 2A13, 2F1, 2S1 and 4B1 are preferentially expressed in the lung together with CYP2E1 and 3A5. This review provides a detailed picture of major xenobiotic-metabolizing phase I (CYPs, epoxide hydrolases, flavin monooxygenases, etc.) and phase II enzymes (conjugation enzymes, including several transferases) expressed in human lung. The roles of individual metabolizing enzymes and their genetic polymorphisms are also discussed.

Multiple dose pharmacokinetics of inhaled loxapine in subjects on chronic, stable antipsychotic regimens

“…28 Intramuscular administration of 20 mg of loxapine resulted in a C max of 17.8 ng/mL after approximately 1 hour. 29 By comparison, inhalation of 5 or 10 mg (normalized to10 mg loxapine) produced a mean C max of 69.3 ng/mL at a median time of 2 minutes (Table 2) following inhalation, so that clinical effects would be expected to occur very quickly. The <8% difference between the 4-and 2-hour concentrations in this study (Table 2) supports the administration of a second dose 2 hours after the first dose.…”

Genetic variation of genes for xenobiotic-metabolizing enzymes and risk of bronchial asthma: the importance of gene–gene and gene–environment interactions for disease susceptibility

“…It seems that the integrated function of the EPHX1, CYP1B1 and CYP2D6 genes and their products promotes a coordinated metabolism of common xenobiotics such as PAH and heterocyclic compounds in the lungs and airways, where these genes are vitally expressed. 19,50 Interestingly, the cluster MDR analysis showed high-order gene-gene interactions between 14 genes for biotransformation enzymes. This finding illustrates a polygenic nature of interactions between XME genes contributing to asthma pathogenesis.…”

“…It is well known that XMEs in various types of cells in the human lung and airways contribute to the in situ activation and inactivation of many chemical toxicants of the environment. 19 Thus, tissues of the respiratory tract, which are exposed to both inhaled and blood-borne xenobiotic compounds, are important targets for environmental toxicity. Therefore, it would be reasonable to propose that considerable interindividual differences in the expression and/or activity of XME genes may contribute substantially to asthma susceptibility.…”

In vivo animal models for drug delivery across the lung mucosal barrier☆

“…In the case of protein and peptide drugs this can mean rapid degradation in the lysosomal system. Drug metabolising enzymes are present in much lower concentrations in the lungs [25] than in the gastrointestinal tract and the degree of drug metabolism appears to be drug-type dependent with small peptides being hydrolysed rapidly while for small molecules metabolism is minimal. A certain degree of metabolic clearance of insulin has been demonstrated in recent kinetic studies which would appear to impact on its <10% bioavailability in both human and animals alongside mucociliary clearance [26].…”