Differential effects of trivalent and pentavalent arsenicals on cell proliferation and cytokine secretion in normal human epidermal keratinocytes

There is strong evidence from epidemiologic studies of an association betwe en chronic exposure to inorganic arsenic (iAs) and hyperpigmentation, hyper keratosis, and neoplasia in the skin. Although it is generally accepted tha t methylation is a mechanism of arsenic detoxification, recent studies have suggested that methylated arsenicals also have deleterious biological effe cts. In these studies we compare the effects of inorganic arsenicals (arsen ite (iAs([I])) and arsenate (iAs(V))) and trivalent and pentavalent methyla ted arsenicals (methylarsine oxide ((MAsO)-O-III), complex of dimethylarsin ous acid with glutathione (DMAs(III)GS), methylarsonic acid (MAsV), and dim ethylarsinic acid (DMAsV)) in human keratinocyte cultures. Viability testin g showed that the relative toxicities of the arsenicals were as follows: iA s(III) > (MAsO)-O-III > DMAs(III)GS > DMAsV > MAsV > iAs(V). Trivalent arse nicals induced an increase in cell proliferation at concentrations in the 0 .001 to 0.01 muM range, while at high concentrations (>0.5 muM) cell prolif eration was inhibited. Pentavalent arsenicals did not stimulate cell prolif eration. As seen in the viability studies, the methylated forms of As-V wer e more cytotoxic than iAs(V). Exposure to low doses of trivalent arsenicals stimulated secretion of the growth-promoting cytokines, granulocyte macrop hage colony stimulating factor and tumor necrosis factor-alpha. DMAsV reduc ed cytokine secretion at concentrations at which proliferation and viabilit y were not affected. These data suggest that methylated arsenicals, product s of the metabolic conversion of inorganic arsenic, can significantly affec t viability and proliferation of human keratinocytes and modify their secre tion of inflammatory and growth-promoting cytokines. (C) 2001 Academic Pres s.