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2,3,7,8-Tetrachlorodibenzo-p-dioxin as Cocarcinogen Causing 3-Methylcholanthrene-initiated Subcutaneous Tumors in Mice Genetically "Nonresponsive" at Ah Locus¹

Department of Biochemical Oncology, Microbiological Associates, Bethesda 20016 [R. E. K., T. H. R., R. J.], and Laboratory of Chemistry, National Institute of Arthritis, Metabolism, and Digestive Diseases [P. M. D., D. M. J.] and Developmental Pharmacology Branch, National Institute of Child Health and Human Development [S. A. A., I. S. O., D. W. N.], Bethesda, Maryland 20014

A high dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) (60 or 100 µg/kg) is known to induce aryl hydrocarbon [benzo(a)pyrene] hydroxylase (EC 1.14.14.2) (AHH) and cytochrome P₁-450 in the liver and in numerous nonhepatic tissues of both genetically "responsive" C57BL/6 and genetically "nonresponsive" DBA/2 mice. A low dose of TCDD (1 µg/kg) is known to induce AHH and P₁-450 in the responsive C57BL/6 tissues but not in the liver and only very little in nonhepatic tissues of the nonresponsive DBA/2 mouse. In the liver of either strain of mice 12 to 48 hr after the high dose of TCDD, the magnitude of increase in AHH is many tisses greater than any change seen in hepatic epoxide hydrase (EC 4.2.1.63), glutathione S-transferase (EC 4.4.1.7), or uridine diphosphate-glucuronosyltransferase (EC 2.4.1.17). The kinetics of AHH induction in skin and s.c. tissue after s.c. administered TCDD is very similar to that in liver of these mouse strains, and the magnitude of AHH induction in skin and s.c. tissue is much greater than that in liver.

At an i.p. dose that kills 30 to 70% of the animals in each group of DBA/2 or C57BL/6 mice, TCDD causes no tumors in the survivors 36 weeks later. i.p. TCDD given to C57BL/6 mice 2 days prior to or simultaneously with s.c. 3-methylcholanthrene (MCA) does not affect the MCA carcinogenic index (which is about 60). i.p. TCDD given to DBA/2 mice 2 days prior to s.c. MCA increases slightly the carcinogenic index (from 5 to 10). s.c. TCDD (100 µg/kg body weight) given simultaneously in the same vehicle with s.c. MCA to DBA/2 mice markedly increases the carcinogenic index (from 5 to 38).

In this test system therefore TCDD appears not to be carcinogenic. We conclude, however, that TCDD is a cocarcinogen. We propose that the mechanism of action is to induce AHH activity and its associated P₁-450 at the site of inoculation of MCA in genetically nonresponsive mice, thereby resulting in more efficient metabolic conversion of MCA to the (proximal or) ultimate carcinogen.

¹ Portions of this work were supported by contracts from The Council for Tobacco Research.

² To whom requests for reprints should be addressed, at Developmental Pharmacology Branch, Room 13-N-234, Building 10, NIH, Bethesda, Md. 20014.

Received 12/19/77. Accepted 6/ 6/78.

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