Cytochromes P4501 (CYP1): catalytic activities and inducibility by diesel exhaust particle extract and benzo[a]pyrene in intact human lung ex vivo.
Catalytic activities of CYP1A1, CYP1A2 and CYP1B1, and inducibility of the activities were studied in intact human lung samples (from 23 human subjects) ex vivo. The activities [as measured by ethoxyresorufin O-deethylase (EROD), methoxyresorufin O-demethylase (MROD), and 3-cyano-7-ethoxycoumarin O-deethylase (CECOD)] were present in the lungs and were induced by benzo[a]pyrene (B[a]P) and diesel exhaust particle extract (DEE) but with extensive inter-subject variability. All three activities were substantially inhibited (>or=75%) by the CYP1 inhibitor alpha-naphthoflavone, whereas only MROD and CECOD were substantially inhibited by the CYP1A2-preferential inhibitor fluvoxamine. None of the three activities was substantially inhibited by the CYP1B1-preferential inhibitor tetramethoxystilbene, indicating lack of involvement of CYP1B1 in the activities in the intact lung. CYP1A1 and CYP1A2 proteins were present in the lungs (by western blot analysis), also with extensive inter-subject variability, and were induced by B[a]P or DEE more extensively than by the combination of B[a]P and DEE (B[a]P+DEE). CYP1B1 was also present in the lungs and its level varied extensively between subjects. In contrast with CYP1A and CYP1A2 levels, CYP1B1 level was not significantly altered by B[a]P or DEE treatment and was diminished more extensively by treatment with B[a]P+DEE. The findings point to the potential usefulness of the intact lung for assessing in situ xenobiotic biotransformation reactions as well as the CYP1 specificity of the reactions ex vivo. The findings also suggest MROD and CECOD as potential markers of CYP1A2 activity in the intact lung.
Iba
Michael M
MM
Department of Pharmacology and Toxicology, Rutgers University, Piscataway, NJ 08854, USA. iba@eohsi.rutgers.edu
Shin
Maria
M
Caccavale
Robert J
RJ
D015660:7-Alkoxycoumarin O-Dealkylase / Q000378:metabolism; D000368:Aged; D000369:Aged, 80 and over; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism*; D001564:Benzo(a)pyrene / Q000633:toxicity*; D002384:Catalysis / Q000187:drug effects; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism*; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism*; D065633:Cytochrome P-450 CYP1B1; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005260:Female; D006801:Humans; D008168:Lung / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D008875:Middle Aged; D052638:Particulate Matter / Q000633:toxicity; D001335:Vehicle Emissions / Q000633:toxicity*
D052638:Particulate Matter; D001335:Vehicle Emissions; D001564:Benzo(a)pyrene; D003577:Cytochrome P-450 Enzyme System; C076307:methoxyresorufin-O-demethylase; D015660:7-Alkoxycoumarin O-Dealkylase; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; D065633:Cytochrome P-450 CYP1B1