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Effect of Extracellular Calcium Concentration on the Metabolism of Polycyclic Aromatic Hydrocarbons by Cultured Mouse Keratinocytes¹

The University of Texas M. D. Anderson Cancer Center, Science Park-Research Division, Smithville, Texas 78957

Cultures of adult mouse epidermal keratinocytes (MEKs) were utilized to determine whether the metabolism and metabolic activation of polycyclic aromatic hydrocarbons varied as a function of extracellular calcium (Ca²⁺) concentration. MEKs grown in low Ca²⁺-containing medium (0.05–0.10 mM) maintain basal cell morphology and proliferate while increasing the Ca²⁺ concentration in the medium to 1.2–1.4 mM signals the cells to undergo terminal differentiation. Relative to cultures of undifferentiated MEKs (low Ca²⁺), cultures of differentiated MEKs that had been switched to high Ca²⁺ medium 48 h prior to treatment with benzo(a)-pyrene [B(a)P] and 7,12-dimethylbenz(a)anthracene (DMBA) exhibited more rapid overall metabolism of both hydrocarbons. The greatest differences in the metabolism of B(a)P and DMBA between the two types of cultures occurred after a 3-6-h lag period. In addition, the levels of DNA-adducts formed from B(a)P and DMBA after a 24-h exposure to the hydrocarbon were 4- and 3-fold higher respectively, in cultures of differentiated MEKs (high Ca²⁺). Higher levels of mutagenesis and cytotoxicity were also observed in cocultures of Chinese hamster lung V-79 cells and MEKs that had been switched to high Ca²⁺-containing medium. In cocultures treated with the hydrocarbons at the time of Ca²⁺ shift, several hours elapsed before differences in mutagenesis were apparent between high and low Ca²⁺-containing cultures. This lag period was eliminated if the MEKs were switched to high Ca²⁺ medium 24 h prior to exposure to DMBA. Based on the present data, we propose that the expression and inducibility of certain enzyme activities involved in the metabolism of B(a)P and DMBA by cultured MEKs is regulated by the extracellular Ca²⁺ concentration and possibly the Ca²⁺-induced differentiation of MEKs.

¹ Research supported by USPHS Grants CA 36979 (JD) and CA 40823 (JJR).

² To whom requests for reprints should be addressed, at The University of Texas M. D. Anderson Cancer Center, Science Park-Research Division, P. O. Box 389, Smithville, TX 78957.

Received 11/14/88. Revised 5/15/89. Accepted 7/21/89.

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