SUBCELLULAR-LOCALIZATION OF TCDD DIFFERS BETWEEN THE LIVER, LUNGS, AND KIDNEYS AFTER ACUTE AND SUBCHRONIC EXPOSURE - SPECIES DOSE COMPARISONS AND POSSIBLE MECHANISM/

Subcellular localization of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related compounds has been examined only in the liver, The object ive of this study was (1) to examine and compare the subcellular distr ibution of TCDD within hepatic and nonhepatic (lungs/kidneys) tissues of female Sprague-Dawley rats acutely exposed to TCDD, (2) to analyze species comparisons in the subcellular localization of TCDD in multipl e tissues, (3) to investigate the effect of dose on subcellular distri bution of TCDD, (4) to analyze the effect of subchronic exposure on th e subcellular distribution of TCDD, and (5) to examine one possible me chanism for subcellular localization of TCDD. Female Sprague-Dawley ra ts and B6C3F1 mice received a single oral dose of 0.1, 1.0, or 10 mu g [H-3]TCDD/kg body weight and subcellular fractions of the liver, lung s, and kidneys were prepared by differential centrifugation 3 days aft er exposure, Analysis of the rat subcellular fractions revealed that T CDD was equally distributed between the hepatic P9 (mitochondrial, lys osomal, and nuclear) and S9 (cytosol and microsomal) fractions at all doses tested. In contrast, TCDD was concentrated in the P9 of rat nonh epatic tissues at all doses studied, Differential centrifugation of th e hepatic S9 showed that TCDD was localized within the hepatic P100 (m icrosomal) fraction at all doses tested, In contrast, TCDD localized i n pulmonary and renal S100 (cytosolic) fractions at all doses. The sub cellular distribution of TCDD in the liver and lungs of acutely expose d B6C3F1 mice was similar to that observed in the rats, Although TCDD was concentrated within the renal P9, the remainder of TCDD in the S9 was evenly distributed between the S100 and the P100 fractions of acut ely exposed B6C3F1 mice, Subchronic exposure of B6C3F1 mice to 1.5 or 150 ng [H-3]TCDD/kg/day revealed that increasing dose resulted in equa l distribution of TCDD between the hepatic S9 and P9 versus concentrat ion in the renal P9. In addition, a dose-dependent increase in accumul ation of TCDD in the hepatic P100 was accompanied by a dose-dependent increase in TCDD localization in the renal S100 of mice subchronically exposed to TCDD. TCDD exposure in rats resulted in a dose-dependent i ncrease in the induction of CYP1A1 protein and associated enzyme activ ity in hepatic, pulmonary, and renal microsomes, TCDD-induced CYP1A2 p rotein levels and associated enzymatic activity were only present in h epatic microsomes, This is the first report to suggest that subcellula r distribution of TCDD differs between hepatic and nonhepatic tissues and demonstrate that the liver-specific microsomal localization of TCD D in female Sprague-Dawley rats also occurs in the liver of female B6C 3F1 mice acutely or subchronically exposed to TCDD. In addition, these data are consistent with the hypothesis that the hepatic sequestratio n of TCDD is due to an interaction with CYP1A2, Furthermore, the lack of pulmonary/renal sequestration coupled with the lack of localization of TCDD in pulmonary/renal microsomes also supports the role of CYP1A 2 as a hepatic microsomal binding protein involved in TCDD sequestrati on. (C) 1996 Society of Toxicology.