Nickel, cadmium, cobalt, and arsenic compounds are well-known carcinogens to humans and experimental animals. Even though their DNA-damaging potentials are rather weak, they interfere with the nucleotide and base excision repair at low, noncytotoxic concentrations. For example, both water-soluble Ni(II) and particulate black NiO greatly reduced the repair of DNA adducts induced by benzo[a]pyrene, an important environmental pollutant. Furthermore, Ni(II), As(III), and Co(II) interfered with cell cycle progression and cell cycle control in response to ultraviolet C radiation. As potential molecular targets, interactions with so-called zinc finger proteins involved in DNA repair and/or DNA damage signaling were investigated. We observed an inactivation of the bacterial formamidopyrimidine-DNA glycosylase (Fpg), the mammalian xeroderma pigmentosum group A protein (XPA), and the poly(adenosine diphosphate-ribose)polymerase (PARP). Although all proteins were inhibited by Cd(II) and Cu(II), XPA and PARP but not Fpg were inhibited by Co(II) and Ni(II). As(III) deserves special attention, as it inactivated only PARP, but did so at very low concentrations starting from 10 nM. Because DNA is permanently damaged by endogenous and environmental factors, functioning processing of DNA lesions is an important prerequisite for maintaining genomic integrity; its inactivation by metal compounds may therefore constitute an important mechanism of metal-related carcinogenicity.

No abstract

Arsenite is a naturally occurring environmental pollutant of major concern, since adverse health effects including cancer of skin and internal organs have been attributed to chronic arsenic exposure especially via drinking water. Arsenite is not a significant inducer of point mutations but exerts clastogenic activities and interferes with various DNA repair systems at concentrations in the low micromolar range. Nevertheless, no single DNA repair protein exquisitely sensitive to arsenic has been identified. Here we report that poly(ADP-ribosyl)ation, which is predominantly mediated by poly(ADP-ribose) polymerase-1 (PARP-1), is inhibited at concentrations as low as 10 nM in cultured HeLa cells, closely matching arsenic concentrations in blood and urine of the general population. Since poly(ADP-ribosyl)ation is an immediate cellular response to DNA damage, playing a major role in DNA base excision repair and the maintenance of genomic stability, its inhibition by arsenite may add to the risk of cancer formation under low-exposure conditions. © 2002 Wiley-Liss, Inc. Key words: arsenic; poly(ADP-ribosyl)ation; PARP; mammalian cellsArsenic compounds have long been recognized to cause adverse health effects to humans. Besides neurotoxicity, liver injury and peripheral vascular disease, known as "blackfoot disease," there is an increased cancer incidence especially associated with arsenic exposure. Significant levels of arsenic exist at a variety of workplaces including copper, zinc and lead smelters or glass manufacturing, as well as during the production and use of pesticides and herbicides. 1 Although the commercial use of arsenicals has been largely reduced over the last decades, there is, nevertheless, persistent environmental concern about high levels of arsenic in drinking water in some regions of Argentina, Canada, India, Japan, Taiwan and Thailand due to natural sources. 2 While exposure to arsenic compounds by inhalation increases the risk of lung cancer, 1 oral ingestion of arsenic has been associated with increased incidence of skin, lung, kidney, bladder and liver tumours. 2,3 However, the mechanism underlying the carcinogenic action is not clear, since arsenic compounds are not significantly mutagenic in bacterial test systems or in mammalian cells in culture. In contrast, their clastogenic potential, causing mainly chromatid-type chromosomal aberrations, sister-chromatid exchanges and micronuclei, is well documented with As(III) being more potent than As(V) (see recent reviews). 4,5 Several studies point to an interaction of arsenic with various DNA repair pathways, which may represent a predominant mechanism of arsenic-induced genotoxicity. For example, arsenite increased the mutation frequency in E. coli when combined with UV light. 6 Also in cultured mammalian cells, arsenic compounds have been shown to enhance the persistence of DNA damage induced by UV-light, benzo[a]pyrene, X-rays, alkylating agents or DNA crosslinking compounds and to potentiate their cytotoxicity, mutagenicity and clastogenicity (...

No abstract

No abstract

No abstract