TY - JOUR
T1 - Tissue distribution, subcellular localization and covalent binding of 2-chloroaniline and 4-chloroaniline in Fischer 344 rats
AU - Dial, Larry D.
AU - Anestis, Dianne K.
AU - Kennedy, Stephen R.
AU - Rankin, Gary O.
N1 - Funding Information:
The authors would like to thank Darla Kuryla for her assistance in the preparation of this manuscript and members of the RFC for their encouragement and suggestions. This work was supported in part by NIH grant ES04954.
PY - 1998/11/16
Y1 - 1998/11/16
N2 - Chloroanilines (CA) are widely used chemical intermediates which induce numerous toxicities including hematotoxicity, splenotoxicity, hepatotoxicity and nephrotoxicity. Although chloroaniline-induced hematotoxicity has been studied in detail, little information is available on the organ-directed toxicity seen following exposure to these agents. The purpose of this study was to examine and compare the excretion and distribution of two nephrotoxicant and hepatotoxicant chloroanilines (2- and 4-chloroaniline) to liver, kidney, spleen, plasma and erythrocytes. Subcellular distribution and covalent binding in kidney and liver were also determined. Male Fischer 344 rats (four per group) were administered [14C]-2-chloroaniline or [14C]-4-chloroaniline (0.5 or 1.0 mmol/kg; ~50 μCi/rat) intraperitoneally (i.p.). Urine, feces, blood and tissues were collected at 3 and 24 h. Both 2- and 4-chloroaniline-derived radioactivity were primarily renally excreted with <1% excretion in the feces by 24 h post-treatment. Both chloroanilines accumulated mainly in liver (percentage of administered dose/total tissue), but kidney generally had similar or higher equivalent concentrations (μmol/g tissue) compared to liver. Subcellular distribution revealed that for both chloroanilines, the cytosolic fraction generally had the highest level of radioactivity independent of time or dose. Covalent binding was detected in both liver and kidney, with the highest concentration (pmol/mg protein) of binding observed in the hepatic microsomal fraction regardless of compound, dose or time studied. In general, 2-chloroaniline derived radioactivity was excreted faster, reached peak tissue concentrations earlier, disappeared from tissues faster and had less covalent binding in target tissue at 24 h than 4-chloroaniline-derived radioactivity. These results suggest that the increased toxic potential of 4-chloroaniline as compared to 2-chloroaniline may be due in part to a more prolonged and persistent accumulation of 4-chloroaniline and/or its metabolites in target tissue. Copyright (C) 1998 Elsevier Science Ireland Ltd.
AB - Chloroanilines (CA) are widely used chemical intermediates which induce numerous toxicities including hematotoxicity, splenotoxicity, hepatotoxicity and nephrotoxicity. Although chloroaniline-induced hematotoxicity has been studied in detail, little information is available on the organ-directed toxicity seen following exposure to these agents. The purpose of this study was to examine and compare the excretion and distribution of two nephrotoxicant and hepatotoxicant chloroanilines (2- and 4-chloroaniline) to liver, kidney, spleen, plasma and erythrocytes. Subcellular distribution and covalent binding in kidney and liver were also determined. Male Fischer 344 rats (four per group) were administered [14C]-2-chloroaniline or [14C]-4-chloroaniline (0.5 or 1.0 mmol/kg; ~50 μCi/rat) intraperitoneally (i.p.). Urine, feces, blood and tissues were collected at 3 and 24 h. Both 2- and 4-chloroaniline-derived radioactivity were primarily renally excreted with <1% excretion in the feces by 24 h post-treatment. Both chloroanilines accumulated mainly in liver (percentage of administered dose/total tissue), but kidney generally had similar or higher equivalent concentrations (μmol/g tissue) compared to liver. Subcellular distribution revealed that for both chloroanilines, the cytosolic fraction generally had the highest level of radioactivity independent of time or dose. Covalent binding was detected in both liver and kidney, with the highest concentration (pmol/mg protein) of binding observed in the hepatic microsomal fraction regardless of compound, dose or time studied. In general, 2-chloroaniline derived radioactivity was excreted faster, reached peak tissue concentrations earlier, disappeared from tissues faster and had less covalent binding in target tissue at 24 h than 4-chloroaniline-derived radioactivity. These results suggest that the increased toxic potential of 4-chloroaniline as compared to 2-chloroaniline may be due in part to a more prolonged and persistent accumulation of 4-chloroaniline and/or its metabolites in target tissue. Copyright (C) 1998 Elsevier Science Ireland Ltd.
KW - Chloroanilines
KW - Distribution
KW - Rats
KW - Reactive intermediates
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U2 - 10.1016/S0300-483X(98)00122-X
DO - 10.1016/S0300-483X(98)00122-X
M3 - Article
C2 - 9928626
AN - SCOPUS:0032538982
SN - 0300-483X
VL - 131
SP - 109
EP - 119
JO - Toxicology
JF - Toxicology
IS - 2-3
ER -