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Molecular Pharmacology, Vol 11, 399-408, Copyright © 1975 by the American Society for Pharmacology and Experimental Therapeutics

Induction of Aryl Hydrocarbon Hydroxylase Activity in Various Cell Cultures by 2,3,7,8-Tetrachlorodibenzo-p-dioxin

AKIRA NIWA 1, KENJI KUMAKI 1, and DANIEL W. NEBERT 1

1 Section on Developmental Pharmacology, Neonatal and Pediatric Medicine Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20014

The kinetics of aryl hydrocarbon (benzo[a]pyrene) hydroxylase induction by 2,3,7,8-tetrachlorodibenzo-p-dioxin. (TCDD) among 10 established cell lines, as well as fetal primary cultures derived from hamster, rat, chick, rabbit, and four inbred strains of mice, and cultured human lymphocytes, is very similar to the time course of hydroxylase induction by 3-methylcholanthrene (MC) as the inducer. The TCDD-inducible process is sensitive to actinomycin D and cycloheximide at levels of inhibitor similar to those previously reported with MC in culture. The induced enzyme activity in cells treated with TCDD plus MC is not greater than that in cells exposed to either inducer alone. There exists no relationship between cytotoxicity by TCDD and the level of inducible hydroxylase activity in culture. Estimated ED50 values for the hydroxylase induction by TCDD range from about 0.12 nM in C57BL/6N mouse cultures and 0.23 nM in the H-4-II-E cell line to more than 100 nM in the VERO and HTC cell lines. No hydroxylase activity is detectable in the control, MC-, or TCDD-treated LB82 cell line. In several cell lines and in primary cultures, the responsiveness of hydroxylase induction to TCDD is between 250 and 900 times greater than that to MC. The responsiveness of hydroxylase induction to TCDD in C57BL/6N mouse-derived cultures is about 16 times greater than the responsiveness to TCDD in DBA/2N mouse-derived cultures; this difference in responsiveness to TCDD is very similar to that seen in these two mouse strains in vivo. A bioassay with H-4-II-E cells is suggested for the detection of minute (10-14 mole) levels of TCDD.

Note:
ACKNOWLEDGMENTS We appreciate valuable discussions with Dr. Alan P. Poland concerning these experiments, and we acknowledge the help of Drs. Richard E. Kouri and Steven A. Atlas in the studies with cultured human lymphocytes.

Submitted on January 13, 1975






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