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 adduc t 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 con sidered to be a critical step in the mechanism of carcinogenesis. Long-lived paramagnetic chromium species, Cr5+, Cr4+, Cr3+ are formed in th e presence of coenzymes such as NAD(P)H, GSH, and cytochromes. These anioni c complexes of reduced chromium are considered potential "penultimate" carc inogens. Various in vitro and in vivo studies from our group have demonstra ted the formation of these ionic species using a modified paramagnetic spec troscopy approach, in this review, information is provided on the half-live s of formation and decay, free energy changes, atomic structures and reacti on mechanisms of these compounds in situ, in vivo and in vitro, at the mole cular, cellular-and organismic levels. Hydroxyl radical ( OH) can be generated from the reaction of these Cr5+, Cr 4+ 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 ra dicals may be generated from reaction of chromium with cellular reductants and peroxides. These radicals, particularly the hydroxyl radical, are consi dered the ultimate agents in chromium carcinogenesis. They may break phosop hodiester 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 ge netic information may also be passed onto future generations through cell r eplications to the daughter cells. Thus. OH from the interaction of Cr5+, C r4+ with H2O2 affects not only differentiation but also cell division, and leads to the development of cancer as a result.