Activation of a procarcinogen by reduction: Cr⁶⁺→Cr⁵⁺→Cr⁴⁺→Cr³⁺. A case study by electron spin resonance (ESR/PMR)

Chromate is a human carcinogen. Since it does not form a covalent DNA adduct in vitro under physiological conditions, and is not mutagenic in vitro in the presence of cytochrome P450 preparations from liver, reduction of Cr⁶⁺ by cellular reductants to lower oxidation states such as Cr⁵⁺, Cr⁴⁺ is considered to be a critical step in the mechanism of carcinogenesis. Long-lived paramagnetic chromium species, Cr⁵⁺, Cr⁴⁺, Cr³⁺ are formed in the presence of coenzymes such as NAD(P)H, GSH, and cytochromes. These anionic complexes of reduced chromium are considered potential 'penultimate' carcinogens. Various in vitro and in vivo studies from our group have demonstrated the formation of these ionic species using a modified paramagnetic spectroscopy approach. In this review, information is provided on the half-lives of formation and decay, free energy changes, atomic structures and reaction mechanisms of these compounds in situ, in vivo and in vitro, at the molecular, cellular and organismic levels. Hydroxyl radical (·OH) can be generated from the reaction of these Cr⁵⁺, Cr⁴⁺ compounds with H₂O₂ by a Fenton-like reaction, as can be demonstrated by molecular spin traps. In addition to ·OH radical, a number of other free radicals may be generated from reaction of chromium with cellular reductants and peroxides. These radicals, particularly the hydroxyl radical, are considered the ultimate agents in chromium carcinogenesis. They may break phosophodiester bonds of the DNA double strands, and modify 2'-deoxyguanosine to form promutagenic 8-hydroxy-2'-deoxyguanosine (8-OHdG) in the DNA structure. Genetic expressions are changed at the transcription level. Changes in genetic information may also be passed onto future generations through cell replications to the daughter cells. Thus, ·OH from the interaction Cr⁵⁺, Cr⁴⁺ with H₂O₂ affects not only differentiation but also cell division, and leads to the development of cancer as a result.