Studies of The Mechanism of Action of Hepatotoxicity of 2,3,7,8- Tetrachlorodibenzo-P-Dioxin (TCDD) and Related Compounds
TCDD causes liver damage, porphyria, chloracne, thymic atrophy and damage to other organs in rats and mice. The porphyria due to TCDD reflects interference with an enzyme, uroporphyrinogen decarboxylase, converting uroporphyrinogen to coproporphyrinogen. We studied TCDD liver toxicity in an inbred strain of mice using histological criteria and porphyria as indices of severity. Toxicity of TCDD was enhanced in C57B1/6J (responsive) mice in comparison with DBA/2J (non-responsive) mice. This difference is attributed to the high affinity binding site in hepatic cytosol of C57 mice. Interaction with this site is required for induction of aryl hydrocarbon hydroxylase (AHH) and other coordinately expressed functions under control of a regulatory gene (‘Ah’) which differs in C57 and DBA mice. We compared the effects of TCDD in C57/B1 mice depleted of iron by venesection with control animals not deficient in iron. Low iron animals were protected against porphyria and liver damage but not against thymic atrophy or chloracne. Dependence upon the Ah gene and on non-heme tissue iron has suggested a free radical mechanism initiating lipid peroxidation. The finding that dietary supplements of butylated hyroxy anisole also protect against histological changes in the liver and porphyria is consistent with this hypothesis.
KeywordsPorphyria Cutanea Tarda High Affinity Binding Site Tissue Iron Thymic Atrophy Aryl Hydrocarbon Hydroxylase
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