Metabolic activation of phenanthrene by human and mouse cytochromes P450 and pharmacokinetics in CYP1A2 knockout mice.
In the present study V79 Chinese hamster cells were genetically engineered for stable expression of the cytochromes P450 1A1, 1A2, 1B1, and 2E1 from man and mouse to investigate species-specific differences in the regioselective metabolism and toxicity of phenanthrene (Phe), the simplest polycyclic aromatic hydrocarbon (PAH) forming a bay-region. Phe is present in various environmental samples and serves as a model substrate for PAH exposure in human biomonitoring studies. For this reason we explored metabolite profiles and metabolite-dependent cytotoxic activities in vitro. The total turnover of CYP-mediated transformation of Phe was as follows: human CYP1B1>CYP1A1>CYP1A2>>CYP2E1, and for mouse CYP1A2>>CYP2E1>CYP1A1. Striking species differences were seen as mouse CYP1B1 did not activate Phe at all, but human CYP1B1 exhibited a significant metabolic turnover comparable to CYP1A1 and CYP1A2. In vivo studies monitoring the whole blood Phe elimination in CYP1A2 knockout and wild-type mice after oral administration confirmed involvement of CYP1A2 in the bioactivation of Phe, but other processes must contribute also. Our data suggest that in humans not only CYP1A2 expressed solely in the liver plays a crucial role in Phe metabolism, but also constitutively expressed extrahepatic CYP1B1 in tissues such as lung, kidney or intestine. This finding will substantially improve the validity of human biomonitoring studies using individual Phe metabolites for the assessment of PAH exposure.
Schober
Wolfgang
W
Division of Environmental Dermatology and Allergy, Helmholtz Zentrum München/TUM, ZAUM - Center for Allergy and Environment, Technische Universität München, Biedersteiner Strasse 29, 80802 Munich, Germany. schober@lrz.tum.de
Pusch
Gudrun
G
Oeder
Sebastian
S
Reindl
Heidi
H
Behrendt
Heidrun
H
Buters
Jeroen T M
JT
D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D019388:Cytochrome P-450 CYP1A2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004784:Environmental Monitoring; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010616:Phenanthrenes / Q000097:blood / Q000378:metabolism / Q000633:toxicity*; D020033:Protein Isoforms / Q000378:metabolism; D013237:Stereoisomerism; D014874:Water Pollutants, Chemical / Q000097:blood / Q000378:metabolism / Q000633:toxicity*
D010616:Phenanthrenes; D020033:Protein Isoforms; D014874:Water Pollutants, Chemical; C031181:phenanthrene; D003577:Cytochrome P-450 Enzyme System; D019388:Cytochrome P-450 CYP1A2