On the species-specific biotransformation of dibenzo[a,l]pyrene.
We were aimed at investigating the activation of the carcinogenic polycyclic aromatic hydrocarbon (PAH) dibenzo[a,l]pyrene (DB[a,l]P) in Chinese hamster V79 cells that express single human, rat or fish cytochrome P450 (CYP) enzymes. DB[a,l]P is detectable in environmental samples and has been characterized as the most potent carcinogenic species among all PAHs as yet tested in rodent bioassays. Metabolite profiles and metabolite-dependent cytotoxic and clastogenic activities were monitored. The total turnover of CYP-mediated transformation of DB[a,l]P was as follows: human CYP1B1>fish CYP1A1 approximately human CYP1A1>>rat CYP1A2>rat CYP1A1. By contrast, enzyme forms that are not classified as being members of family CYP1, such as CYP2A6, 2E1, 2B1, and 3A4, failed to catalyze any detectable conversion of this substrate. All CYP1A1 enzymes tested formed both the K-region trans-8,9- and the trans-11,12-dihydrodiol, whereas human CYP1B1 failed to catalyze K-region activation. In cells expressing human or fish CYP1A1, human CYP1B1, and rat CYP1A2, the (-)-trans-11,12-dihydrodiol was formed enantiospecifically. DB[a,l]P-dependent cytotoxicities (EC(50)) were found in the following order: human CYP1A1 (12 nM)>fish CYP1A1 (30 nM)>human CYP1B1 (45 nM)>>other forms. In addition, an appreciable micronuclei formation was detected in human CYP1A1- and 1B1-expressing cells during exposure to DB[a,l]P. Our study demonstrates that human CYP1A1, 1B1 and fish CYP1A1 are able to transform DB[a,l]P into genotoxic derivatives in appreciable amounts. In contrast, CYP enzymes from rat predominantly target the K-region of DB[a,l]P and thus are serving more a rather protective route of biotransformation. Together our data suggest that humans might be more susceptible to DB[a,l]P-induced carcinogenicity than rats.
Schober
Wolfgang
W
Division of Environmental Dermatology and Allergy GSF/TUM, ZAUM-Center for Allergy and Environment, Technical University of Munich, Germany. schober@lrz.tum.de
Luch
Andreas
A
Soballa
Volker J
VJ
Raab
Gottfried
G
Stegeman
John J
JJ
Doehmer
Johannes
J
Jacob
Jürgen
J
Seidel
Albrecht
A
D000818:Animals; D001580:Benzopyrenes / Q000493:pharmacokinetics* / Q000633:toxicity; D001711:Biotransformation; D002273:Carcinogens / Q000493:pharmacokinetics* / Q000633:toxicity; D002460:Cell Line; D002470:Cell Survival; D006224:Cricetinae; D003412:Cricetulus; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D006801:Humans; D015162:Micronucleus Tests; D010473:Perciformes; D051381:Rats; D013045:Species Specificity
D001580:Benzopyrenes; D002273:Carcinogens; D003577:Cytochrome P-450 Enzyme System; C041517:dibenzo(a,l)pyrene