Jr. Landolph, MOLECULAR MECHANISMS OF TRANSFORMATION OF C3H 10T1/2 C18 MOUSE EMBRYOCELLS AND DIPLOID HUMAN FIBROBLASTS BY CARCINOGENIC METAL-COMPOUNDS/, Environmental health perspectives, 102, 1994, pp. 119-125
Carcinogenic arsenic, nickel, and chromium compounds induced morpholog
ical and neoplastic transformation but no mutation to ouabain resistan
ce in 10T1/2 mouse embryo cells, lead chromate also did not induce mut
ation to ouabain or 6-thioguanine resistance in Chinese hamster ovary
cells. The mechanism of metal-induced morphological transformation was
likely not due to the specific base substitution mutations measured i
n ouabain resistance mutation assays, and for lead chromate, likely no
t due to this type of base substitution mutation or to frameshift muta
tions. Preliminary data indicate increases in steady-state levels of c
-myc RNA in arsenic-, nickel-, and chromium-transformed cell lines. We
also showed that carcinogenic nickel, chromium, and arsenic compounds
and N-methyl-N-nitro-N-nitrosoguanidine (MNNG) induced stable anchora
ge independence (At) in diploid human fibroblasts (DHF) but no focus f
ormation or immortality. Nickel subsulfide and lead chromate induced A
l but not mutation to 6-thioguanine resistance. The mechanism of induc
tion of Al by metal salts in DHF was likely not by the type of base su
bstitution or frameshift mutations measured in these assays. MNNG indu
ced Al, mutation to 6-thioguanine resistance, and mutation to ouabain
resistance,and might induce Al by base substitution or frameshift muta
tions. Dexamethasone, aspirin, and salicylic acid inhibited nickel sub
sulfide, MNNG, and 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced
Al in DHF, suggesting that arachidonic acid metabolism and oxygen radi
cal generation play a role in induction of Al. We propose that nickel
compounds stimulate arachidonic acid metabolism, consequent oxygen rad
ical generation, and oxygen radical attack upon DNA. Intracellular red
uction of Cr(VI) to Cr(V) or other species that generate oxygen radica
ls leads to CF(V) or oxygen radical attack upon DNA. Arsenite causes c
hromosome breaks. We propose that arsenic, nickel, and chromium compou
nds then cause small deletions or mutations in the 5' or 3' regulatory
regions of the c-myc and other protooncogenes, resulting in stabiliza
tion of c-myc RNA and higher steady-state levels of c-myc RNA and prot
ein. We also postulate that nickel-induced oxygen radical generation,
Cr(V) ions or oxygen radicals generated by chromium, and arsenite indu
ce inactivating mutations or deletions in tumor suppressor genes. Arse
nic, nickel, or chromium compound-induced neoplastic transformation is
postulated to proceed through a combination of activation of c-myc an
d/or other protooncogenes and inactivation of tumor suppressor.