Induction of Cytochrome CYPIA1 and Formation of Toxic Metabolities of Benzo[a]pyrene by Rat Aorta: A Possible Role in Atherogenesis

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 91; no. 12; pp. 5397 - 5401
• Main Authors: Thirman, Michael J., Albrecht, Jeffrey H., Krueger, Michele A., Erickson, Richard R., Cherwitz, David L., Park, Sang S., Gelboin, Harry V., Holtzman, Jordan L.
• Format: Journal Article
• Language: English
• Published: National Academy of Sciences of the United States of America 07-06-1994
• Subjects: Aorta; Atherosclerosis; Cellular metabolism; Cigarette smoking; Cigarettes; Cytochromes; Liver; Metabolism; Metabolites; Microsomes
• ISSN: 0027-8424; 1091-6490

Cigarette smoking is a leading risk factor for atherosclerosis. Endothelial injury may be the initial event in this process. The carcinogenic metabolites of the polycyclic aromatic hydrocarbons found in cigarette smoke tars could cause this injury. We tested this model by examining the effect of 3-methylcholanthrene administration on aortic polycyclic aromatic hydrocarbon metabolism. Immunoblotting with a monoclonal antibody (mAb 1-7-1) specific for cytochromes CYPIA1 and CYPIA2 showed that aortic microsomes from treated, but not from control, animals contained CYPIA1; the CYPIA1 was primarily in the endothelium. Aortic microsomes from induced animals metabolized benzo[a]pyrene (BaP) to the 7R,8S,9,10-tetrahydrotetrol-, 7,8-dihydrodiol-, 1,6 quinone-, 3,6 quinone-, 6,12 quinone-, 3-hydroxy-, and 9-hydroxy-BaP. mAb 1-7-1 inhibited the formation of the tetrahydrotetrol, the dihydrodiol-BaP, and the 3-hydroxy-BaP but did not inhibit the quinones or the 9-hydroxy-BaP. Arachidonic acid did not affect metabolism. These data suggest that the aortas of induced animals metabolize the BaP in cigarette smoke to carcinogenic and toxic products and that this metabolism may initiate vessel injury and lead to the accelerated atherosclerosis seen in cigarette smokers.