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Title: Characterisation of the principal human pulmonary drug-oxidising enzymes, CYP3A5, CYP2B6 & FMO
Author: McCully, S.
Awarding Body: University of Aberdeen
Current Institution: University of Aberdeen
Date of Award: 1999
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Abstract:
The human lung has been shown to possess a wide range of enzyme systems and the potential to metabolise xenobiotics. Despite this, there is a paucity of well-designed investigations on the expression of pulmonary xenobiotic-metabolising enzymes. This thesis aimed to characterise the principal pulmonary drug-oxidising enzymes (CYP3A5, CPY2B6 & FMO) and to assess the role of this organ in the metabolism of therapeutic agents. CYP3A5 and CYP2B6 mRNAs were detected in 75% and 100% of lungs, respectively, and CYP3A5 and CYP2B6 protein was detected in 33% of lung samples, with 11% samples coexpressing these enzymes. Testosterone 6β-hydroxylation (CYP3A4/5) and 16β-hydroxylation (CYP2B6/7) were approximately 1500- and 700-fold lower in lung than liver, respectively. FMO activity was 29-fold lower in lung microsomes compared with liver. The ability of human lung microsomes to metabolise KC11458, terfenadine, cyclophosphamide and ifosfamide was investigated. KC11458 was metabolised to KC13195 in human lung samples by CYP2B6, whereas KC11458 was primarily metabolised to metabolite 1 by CYO3A4/5 and FMO in human liver. No terfenadine metabolites were detected in human lung incubations, whereas terfenadine alcohol formation was detected in all 8 livers. Human liver samples activated both ifosfamide and cyclophosphamide, whereas only ifosfamide activation was detected in human lung microsomes. This is of interest as lung cancer is the biggest cause of cancer mortality worldwide and ifosfamide is important in cancer therapy. CYP3A expression has been demonstrated in lung tumours, suggesting ifosfamide could be activated in situ. This study has illustrated the functional expression of specific drug-oxidising enzymes within the lung and has demonstrated that his organ can biotransform and bioactivate therapeutic agents with a metabolite profile significantly different from that of the liver. This may have clinical significance and may be important in determining the activation of compounds having local toxic or therapeutic actions within the lung (e.g. ifosfamide).
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.593066  DOI: Not available
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