Chromium carcinogenesis: Mechanisms and biomonitoring

Whilst chromium (Cr) compounds (particularly water soluble complexes) have long been recognised as carcinogens, much information is still missing about how these agents exert their mutagenic, carcinogenic, and deoxyribonucleic acid (DNA) damaging effects. The activation of Cr(VI) by intracellular reductants such as glutathione (GSH), ascorbic acid (AsA) and cysteine (Cys), among others, is crucial for the mediation of its DNA damaging effects. Studies into the interaction of Cr(VI) with isolated DNA in the presence of GSH were principally concerned with identifying the existence of a mutual mechanistic pathway for the mediation of more than one type of prevalent DNA lesion. The role of reactive oxygen species in the mediation of Cr(VI)-induced DNA damage was considered with particular emphasis on single strand breaks (SSB) and apurinic/apyrimidinic sites (AP-sites). The potential sites of interaction of damaging species with the DNA macromolecule were considered, and from these and other studies several conclusions were drawn. It is demonstrated that Cr-DNA adducts can be formed independently of the reaction pathways giving rise to SSB and AP- sites, and that Cr(V), and possibly Cr(IV) species, as well as hydrolysing Cr(III)/GSH complexes are responsible for the formation of Cr-DNA adducts. Evidence is also provided to support the hypothesis that DNA-phosphate groups are the binding site of Cr-DNA adducts. A bacterial mutation assay was employed to investigate the mutagenic potential of different types of Cr(VI)-induced DNA damage and it was demonstrated that DNA lesions induced during the in vitro conversion of Cr(VI) by GSH can be fixed into mutations during replication and passed onto progeny cells. There is an apparent role for Cr-DNA adduct formation in this process and since Cr(III) species are involved in the mediation of this type of damage it is proposed that Cr(III) represents a species with the potential capacity to cause fixed mutations in cell lines. A novel whole animal model, involving the application of magnetic resonance imaging (MRI), was developed to enable levels of Cr compounds to be monitored in the lung. The technique was shown to be sensitive enough to detect amounts of Cr(III) as low as 5 μg per whole lung. In addition, this method was able to monitor the conversion of Cr(VI) to Cr(III) in situ despite post-mortem conditions; an important finding since it not only demonstrates the powerful reductive capacity of the lung but allows the detection of Cr(VI) which has been shown to be the primary damaging species in Cr-induced carcinogenesis