Oxidative renal tubular injuries induced by aminocarboxylate-type iron (III) coordination compounds as candidate renal carcinogens.

Oxidative renal tubular injuries and carcinogenesis induced by Fe(III)-nitrilotriacetate (NTA) and Fe(III)-ethylenediamine-N,N'-diacetate (EDDA) have been reported in rodent kidneys, but the identity of iron coordination structure essential for renal carcinogenesis, remains to be clarified. We compared renal tubular injuries caused by various low molecular weight aminocarboxylate type chelators with injuries due to NTA and EDDA. We found that Fe(III)-iminodiacetate (IDA), a novel iron-chelator, induced acute tubular injuries and lipid peroxidation to the same extent. We also prepared Fe(III)-IDA solutions at different pHs, and studied resultant oxidative injuries and physicochemical properties. The use of Fe(III)-IDA at pH 5.2, 6.2, and 7.2 resulted in renal tubular necrosis and apoptotic cell death, but neither tubular necrosis nor apoptosis was observed at pH 8.2. Spectrophotometric data suggested that Fe(III)-IDA had the same dimer structure from pH 6.2 to 7.2 as Fe(III)-NTA; but at a higher pH, iron polymerized and formed clusters. Fe(III)-IDA was crystallized, and this was confirmed by X-ray analysis and magnetic susceptibility measurements. These data indicated that Fe(III)-IDA possessed a linear mu-oxo bridged dinuclear iron (III) around neutral pH.

Bioactivation mechanism of L-thiomorpholine-3-carboxylic acid.

L-Thiomorpholine-3-carboxylic acid (L-TMC) is a cyclized analog of S-(2-chloroethyl)-L-cysteine, which is cytotoxic in vitro and nephrotoxic in vivo. To determine whether L-TMC may play a role in S-(2-chloroethyl)-L-cysteine-induced toxicity, the cytotoxicity of L-TMC was studied in isolated rat kidney cells. L-TMC produced time- and concentration-dependent cytotoxicity. Probenecid, an inhibitor of the renal anion transport system, and L-alpha-hydroxyisocaproic acid, a substrate for L-amino acid oxidase, inhibited L-TMC-induced cytotoxicity. Rat kidney cytosol catalyzed the metabolism of L-TMC to a product absorbing at 300 nm. The increase in absorbance at 300 nm was accompanied by an increase in oxygen consumption and was inhibited by L-alpha-hydroxyisocaproic acid; moreover, the absorbance of the metabolite was quenched by addition of potassium cyanide or sodium borohydride, which indicated the formation of an imine. When L-TMC was incubated with rat kidney cytosol and sodium borodeuteride was added at the end of the incubation period, analysis by gas chromatography/mass spectrometry of the tert-butyldimethylsilyl ester of L-TMC showed the formation of [2H]TMC, indicating the intermediate formation of the imine 5,6-dihydro-2H-1,4-thiazine-3-carboxylic acid; chemically synthesized TMC imine showed similar behavior. The enzyme responsible for the metabolism of L-TMC was purified from rat kidney and was identified as L-amino acid oxidase. These observations indicate a role for L-amino acid oxidase in the bioactivation and cytotoxicity of L-TMC.

The acute toxicity of Bimida, a prospective hepatobiliary scanning agent.

The acute toxic effects of dimethyl benzimidazolyl methyliminodiacetic acid (Bimida), a prospective hepatobiliary scanning agent when labelled with 99mTc, are described. The LD50 in male and female rats was 150 mg/kg, and in mice 100 mg/kg, males, and 75 mg/kg, females, up to 2000 times the diagnostic dose required in patients. Clinical signs associated with administration of lethal and sublethal doses of Bimida suggested the cause of death to be an acute hypocalcaemic episode; this was confirmed in vivo and in vitro. A significant reduction in alkaline phosphatase (ALP) activity and Ca2+ concentration associated with administration of 100 human equivalent doses (HED) Bimida and 99mTc labelled Bimida was measured in serum and microsomal preparations of liver and intestine. An in vitro system indicated that this response was prevented in the presence of adequate Ca2+, suggesting that ALP activity is depressed because chelation of the metal ion by Bimida causes a shortage of the Ca2+ needed to activate the enzyme.

Comparative in vivo kinetics of some new 99mTc-labelled acetanilido iminodiacetates.

The in vivo kinetics of five new 99mTc-labelled acetanilido iminodiacetates, analogous to 99mTc-p-butyl IDA, were studied in experimental animals by means of their distribution in mice and scintigrams of rabbits. The new compounds were specifically eliminated via the hepatobiliary system with various rates of hepatic extraction. Urinary excretion of the complexes was minimal.

Toxicity of chelated mercury.

The oral and iv acute toxicities of several mercury chelates were determined in mice in a search for relationships bearing on the effectiveness of various chelating agents in therapy. It was found that the toxicity was independent of the stability constant for the mercury chelate when the toxicity was expressed on a molar basis. For the mercury chelates of sulfhydryl containing chelating agents, the oral toxicity was unexpectedly low, presumably due to the poor absortion of these materials from the G.I. tract. The results suggest that the toxicities of mercury complexes are independent of the stability constant of the complex over the range of stability constant from 10(23) on down, provided chelation does not drastically alter the distribution of the complex in the body.