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Chromium Induces a Persistent Activation of Mitogen-activated Protein Kinases by a Redox-sensitive Mechanism in H4 Rat Hepatoma Cells¹

Department of Pharmacology and Toxicology, Environmental and Occupational Health Sciences Institute, Rutgers University, Piscataway, New Jersey 08855

Chromium is an important industrial metal, an environmental pollutant, and a human carcinogen. To investigate the mechanisms of chromium-induced carcinogenesis, activation of mitogen-activated protein (MAP) kinases ERK1 and ERK2 was examined in rat hepatoma cells following exposure to hexavalent chromium (Cr(VI)). Cr(VI) was found to activate both forms of MAP kinase in a dose- and time-dependent manner. In contrast to the protein kinase C (PKC) agonist, phorbol 12-myristate 13-acetate, which induced a transient activation of MAP kinases, Cr(VI) caused persistent activation of these enzymes. Furthermore, unlike phorbol 12-myristate 13-acetate, the ability of chromium to activate MAP kinases was found to be independent of PKC since chromium-induced MAP kinase activation occurred in PKC-depleted cells. Stimulation of ERK1 and ERK2 was associated with the ability of Cr(VI) to increase cellular peroxide levels as determined using the H₂O₂-sensitive fluorescent probe 2',7'-dichlorofluorescein diacetate and flow cytometry. Furthermore, the activation of these kinases by chromium was enhanced in cells treated with the glutathione-depleting agent, L-buthionine-[S,R]-sulfoximine, and attenuated in cells pretreated with an agent that elevates cellular levels of glutathione (i.e., N-acetyl-L-cysteine). The ability of chromium to modulate MAP kinase activity in this manner suggests a mechanism of chromium-induced carcinogenesis that involves the persistent stimulation of cellular regulatory pathways.

¹ This work was supported, in part, by Grant 690-043 from the New Jersey Commission on Cancer Research (to E.J.Y.) and Grant B11/I-93 from the Diabetes Research and Education Foundation (to E. J. Y.). Additional funding was provided by NIEHS Center of Excellence Grant ES-05022.

² To whom requests for reprints should be addressed, at Environmental and Occupational Health Sciences Institute, 681 Frelinghuysen Road, Piscataway, NJ 08855-1179. Phone: (908) 445-0212; Fax: (908) 445-2534.

Received 10/ 5/95. Accepted 3/ 4/96.

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