Inhibition of lead chromate clastogenesis by ascorbate: relationship to particle dissolution and uptake.
Chromium metal salts are considered to be human carcinogens, especially the salts of low solubility. Lead chromate, a highly insoluble chromium metal salt, has been shown to be tumorigenic, genotoxic and clastogenic. In this study, the roles of particle-cell contact, particle dissolution and particle uptake in the clastogenic activity of lead chromate were investigated. Using Pb51CrO4 it was found that lead chromate particles (1.2 microns mean diameter, -28 mV surface charge) were slightly soluble in water; solubility increased 2-fold when particles were incubated in culture medium, but was not increased further by the addition of serum. The extracellular concentration of chromium increased 7-fold when lead chromate was incubated in the presence of Chinese hamster ovary (CHO) cells compared with culture medium alone. The intracellular concentration of ionic chromium increased in a dose-dependent manner following exposure of CHO cells to clastogenic doses of lead chromate reaching estimated levels as high as 1.2 mM per cell. Treatment of cells with lead chromate particles in the presence of a nontoxic dose of vitamin C blocked uptake of ionic chromium and eliminated the clastogenic activity of the particles. Transmission electron microscopy showed that lead chromate particles were internalized by CHO cells in phagocytic vacuoles in as little as 1 h; internalization was unaffected by co-treatment with vitamin C. It was demonstrated that particle-cell contact was required for lead chromate-induced clastogenesis. These data show that although phagocytic particle uptake occurs, particle-cell contact and extracellular dissolution are responsible for the clastogenic activity of lead chromate. These data also demonstrate that the genotoxicity of particulate hexavalent chromates can be blocked by vitamin C.
Wise
J P
JP
Department of Pharmacology, George Washington University Medical Center, Washington, DC 20037.
Orenstein
J M
JM
Patierno
S R
SR
D000818:Animals; D016587:Antimutagenic Agents / Q000494:pharmacology*; D001205:Ascorbic Acid / Q000494:pharmacology*; D016466:CHO Cells; D002840:Chromates / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity*; D002857:Chromium / Q000493:pharmacokinetics; D006224:Cricetinae; D004249:DNA Damage; D007854:Lead / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity*; D016296:Mutagenesis / Q000187:drug effects*; D010316:Particle Size; D012995:Solubility
D016587:Antimutagenic Agents; D002840:Chromates; D002857:Chromium; D007854:Lead; C031895:lead chromate; D001205:Ascorbic Acid