Effect of glutathione modulation of the distribution and transplacental uptake of 2-[14C]-chloroacetonitrile (CAN) quantitative whole-body autoradiographic study in pregnant mice.
Chloroacetonitrile (CAN), a drinking water disinfectant by-product, has mutagenic and carcinogenic properties. CAN is known to deplete glutathione (GSH), and previous studies reported an enhanced molecular interaction of CAN after GSH depletion in the uterine and fetal tissues of mice. The present report may help to understand the potential mechanisms involved in such molecular interactions by examining the disposition, transplacental uptake and covalent interaction of the chemical in normal and GSH depleted pregnant mice (at 13th day of gestation). Both normal and GSH depleted (by administration of Diethylmaleate (DEM), 0.6 mL/kg, i.p.) pregnant mice were given an equitoxic i.v. dose of 2-[14C]-CAN(333 microCi/kg equivalent to 77 mg/kg). Animals were processed for whole-body autoradiography (WBA) at 1, 8 and 24 hr after treatment. Tissue distribution of radioactivity in the autoradiographs was quantitated using computer aided image analysis. With few exceptions, a rapid high uptake (at 1 hr) of radioactivity was observed in all major maternal (liver, lung, urinary bladder, gastrointestinal mucosa, cerebellum, uterine luminal fluid) and fetal (liver, brain) organs of both normal and GSH depleted mice. This pattern of distribution was observed, with lesser intensity, at 8 hr following treatment. At a later time period (24 hr), there was a significant higher retention and covalent interaction of radioactivity in GSH depleted mouse tissues especially in the liver as compared to normal mouse. This study suggests that 2-[14C]-CAN and/or its metabolites are capable of crossing the placental barrier. The observed higher uptake and retention of the radioactivity in the maternal liver, kidney, cerebellum, nasal turbinates and fetal liver may pose toxicity of the chemical to these organs. The increased covalent interaction of radioactivty in GSH depleted mice liver may indicate the potential utilization of GSH pathway by this organ in the detoxication of CAN derived metabolites and thus exerting hepatotoxicity.
Jacob
S
S
Department of Pathology, University of Texas Medical Branch, Galveston 77555-0609, USA. sjacob.utmb.edu
Abdel-Aziz
A A
AA
Shouman
S A
SA
Ahmed
A E
AE
D000097:Acetonitriles / Q000493:pharmacokinetics* / Q000633:toxicity; D000818:Animals; D001345:Autoradiography; D002250:Carbon Radioisotopes; D005260:Female; D005978:Glutathione / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects; D008431:Maternal-Fetal Exchange; D051379:Mice; D011247:Pregnancy; D014018:Tissue Distribution; D014881:Water Supply / Q000592:standards
D000097:Acetonitriles; D002250:Carbon Radioisotopes; C069277:chloroacetonitrile; D005978:Glutathione