Analysis of CYP2D6 expression in human lung: implications for the association between CYP2D6 activity and susceptibility to lung cancer.
We have studied whether CYP2D6 is expressed in human lung tissue, using a specific and sensitive reverse transcriptase-polymerase chain reaction method and immunohistochemistry. Seven out of the eight patients were extensive metabolizers as shown by genotyping for the CYP2D6 (debrisoquine-sparteine) polymorphism. To investigate whether expression of CYP2D6 in lung tumours is different from that in normal lung tissue, tumour tissue samples were also obtained from the same eight patients. Correctly spliced CYP2D6 mRNA was detected by RT-PCR analysis in human liver and duodenum but not in any of the lung samples. In accordance with these negative results, immunoreactivity for CYP2D6 protein, using specific monoclonal and polyclonal antibodies, was very low or absent. No specific cell type of lung tissue showed strong immunoreactivity for CYP2D6, although expression of CYP3A could be clearly demonstrated in the same tissue samples. Moreover, a Western blot analysis revealed no signal in lung microsomes from two additional extensive metabolizers. Taken together, these results indicate that expression of CYP2D6 in human lung is absent or very low. These findings thus argue against a significant local metabolic activation of procarcinogenic agents by CYP2D6 in the lung.
Kivistö
K T
KT
Dr Margarete Fischer-Bosch-Institut für Klinische Pharmakologie, Stuttgart, Germany.
Griese
E U
EU
Stüven
T
T
Fritz
P
P
Friedel
G
G
Kroemer
H K
HK
Zanger
U M
UM
D000368:Aged; D015153:Blotting, Western; D019389:Cytochrome P-450 CYP2D6 / Q000096:biosynthesis* / Q000737:chemistry; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry; D004198:Disease Susceptibility; D005260:Female; D005838:Genotype; D006801:Humans; D007150:Immunohistochemistry; D008168:Lung / Q000166:cytology / Q000201:enzymology* / Q000473:pathology; D008175:Lung Neoplasms / Q000201:enzymology* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000737:chemistry; D016133:Polymerase Chain Reaction
D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D019389:Cytochrome P-450 CYP2D6; C043872:bufuralol 1'-hydroxylase