ARS | Publication request: COMPARISON OF OVERALL METABOLISM OF 1,2,3,7,8-PECDD IN CYP1A2 (-/-) KNOCKOUT AND C57BL/6N PARENTAL STRAINS OF MICE

Submitted to: Organohalogen Compounds
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: January 1, 2003
Publication Date: January 1, 2003
Citation: Hakk, H., Diliberto, J. 2003. Comparison of overall metabolism of 1,2,3,7,8-pecdd in cyp1a2 (-/-) knockout and c57bl/6n parental strains of mice. Organohalogen Compounds. 64:293-296.

Interpretive Summary: 1,2,3,7,8-Pentachlorodibenzo-p-dioxin (PeCDD)is among the most toxic substances ever tested in laboratory animals. The high toxicity is exacerbated by the long whole-body half-life and limited metabolism. A primary reason for the long half-life of TCDD is thought to be the fact that it is sequestered by a liver protein called cytochrome P4501A2. Is the sequestration of PeCDD making it unavailable for metabolism by other metabolizing enzymes? This hypothesis was investigated by obtaining mice which lacked the cytochrome P4501A2 protein and comparing overall metabolism of PeCDD with a normal strain of mouse. The results of the study were that one-tenth as much PeCDD remained in the liver at 96h in mice which lacked the cytochrome P4501A2 protein compared to normal mice. The reverse was true of the fatty reserves in the body, where the cytochrome P4501A2 deficient mice had high concentrations of PeCDD, while the normal mice had relatively low concentrations of PeCDD. Overall metabolism was quantified in the urine and feces of both study groups of mice. The results indicated that the normal strain of mouse had a slightly higher level of overall metabolism than the cytochrome P4501A2 deficient mouse (15% vs. 8%)and is consistent with previous work with the most toxic dioxin congener, i.e. 2,3,7,8-tetrachlorodibenzo-p-dioxin. This contradicts the hypothesis that was forwarded and leads to the conclusion that PeCDD is rapidly deposited in fatty tissues in the absence of the liver sequestration protein and has an inherently low level of metabolism in mammals.

Technical Abstract: 1,2,3,7,8-Pentachlorodibenzo-p-dioxin (PeCDD)is among the most toxic substances ever tested in laboratory animals and leads to immune suppression, reproductive abnormalities, and thymic atrophy. In addition, PeCDD has a long whole-body half-life and limited metabolism. The long half-life of PeCDD is partially due to its sequestration by hepatic cytochrome P4501A2 (1A2). The present study attempted to determine whether PeCDD has an inherently poor metabolism or is unavailable for metabolism by virtue of sequestration by 1A2. 14C-TCDD (116 micrograms/kg)was administered orally to a genetically-engineered, 1A2-deficient mouse (KO) and the normal, parental strain (C57BL/6N). Only 6.8% of the dose deposited in liver in KO mice at 96h, while 56.8% was deposited in C57BL/6N liver. Higher extrahepatic concentrations of PeCDD were observed in each tissue sampled in KO mice and ranged from 28% higher in the fat to nearly 600% more in the thymus. These data support the conclusion that 1A2 is the hepatic binding species for PeCDD. Overall metabolism was also quantified in the urine and feces of both study groups of mice. The results indicated that the C57BL/6N mice had a slightly higher level of overall metabolism than the KO mice (15.0% vs. 7.8%). This contradicts the hypothesis that was forwarded, and leads to the conclusion that PeCDD is rapidly deposited in fatty tissues in the absence of the liver sequestration protein and has an inherently low level of metabolism in mammals.