TY - JOUR
T1 - 2,3,7,8-Tetrachlorodibenzo-p-dioxin as Cocarcinogen Causing 3-Methylcholanthrene-initiated Subcutaneous Tumors in Mice Genetically “Nonresponsive” at Ah Locus
AU - Dansette, Patrick M.
AU - Jerina, Donald M.
AU - Atlas, Steven
AU - Owens, Ida S.
PY - 1978/9
Y1 - 1978/9
N2 - A high dose of 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD) (60 or 100 μg/kg) is known to induce aryl hydrocarn bon [benzo(a)pyrene] hydroxylase (EC 1.14.14.2) (AHH) and cytochrome P,-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 nonhepatlc 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 times 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.
AB - A high dose of 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD) (60 or 100 μg/kg) is known to induce aryl hydrocarn bon [benzo(a)pyrene] hydroxylase (EC 1.14.14.2) (AHH) and cytochrome P,-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 nonhepatlc 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 times 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.
UR - https://www.scopus.com/pages/publications/0018072908
M3 - Article
C2 - 679184
AN - SCOPUS:0018072908
SN - 0008-5472
VL - 38
SP - 2777
EP - 2783
JO - Cancer Research
JF - Cancer Research
IS - 9
ER -