| Popis: |
Exposure to complex mixtures has been associated with an increase in the number of cancer mortalities. Complex mixtures, produced from the incomplete combustion of organic matter, consist of homocyclic and heterocyclic polycyclic aromatic hydrocarbons (PAHs). They can be represented by benzo[a]pyrene (BaP) and 7H-dibenzo[c,g]carbazole (DBC), respectively. Both PAHs have been detected in cigarette smoke and automobile exhaust. To exert their biological effects, PAHs must be metabolized into reactive intermediates, in which the formation of DNA adducts has been used as an indicator. One of the objectives of this investigation was to study the initial effect of in vivo metabolism of a mixture of DBC and BaP using DNA adduct detection as the tool. This is due to recent work by others suggesting that the effect of a mixture of PAHs (DBC and BaP) did not agree with previous assumptions that the effect would be additive, leading to the hypothesis the metabolism of BaP is interfering with the activation of DBC. One approach used was to determine the biological significance of DBC-3,4-dione. Activation to o-quinones is thought to be one of the mechanisms of PAH activation and others shown that BaP can be activated to this reactive metabolite. As our lab has successfully synthesized an o-quinone of DBC (DBC-3,4-dione), the biological significance of DBC-3,4-dione was determined. To generate o-quinones, the parent PAH has to be initially activated into the appropriate substrates. Previous in vitro studies have suggested that the cytochrome P450 1A1 and 1A2 might be involved in the initial activation. Thus, the contribution of each enzyme in the metabolism of DBC was investigated. |
