Initiation mutagenic mechanism

The key to hexavalent chromium s mutagenicity and possible carcinogenicity is the abiHty of this oxidation state to penetrate the cell membrane. The Cr(VI) Species promotes DNA strand breaks and initiates DNA—DNA and DNA-protein cross-links both in cell cultures and in vivo (105,112,128—130). The mechanism of this genotoxic interaction may be the intercellular reduction of Cr(VI) in close proximity to the nuclear membrane. When in vitro reductions of hexavalent chromium are performed by glutathione, the formation of Cr(V) and glutathione thiyl radicals are observed, and these are beHeved to be responsible for the formation of the DNA cross-links (112). 

One important point of controversy in risk extrapolation is the existence of the threshold level for carcinogenic and mutagenic response to a pollutant. Some argue that an organism is able to cope with low doses of a substance through metabolic processes or repair mechanisms, so that harmful effects do not appear until a certain minimum threshold, or "safe dose", is surpassed. Others contend that a carcinogenic substance must be considered potentially harmful at any dose, and that even a single molecule may initiate a tumor at the cellular level. This is the so-called "one-hit" hypothesis. 

Two mechanisms of 5-bromouracil (BU)-induced mutagenesis, (a) During replication, BU in its usual keto form substitutes for T, and the replica of an initial A-T pair becomes an A-BU pair. In the first mutagenic round of replication, BU in its rare enol form pairs with G. In the next round of replication, the G pairs with a C, completing the transition from an A-T pair to a G-C pair, (b) During replication of a G-C pair, a BU in its rare enol form pairs with a G. In the next round of replication, the BU is again in the common keto form and it pairs with A, so the initial G-C pair becomes all A-T pair. The replica of the A-BU pair produced in the next round of replication is another A-T pair. 

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