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D E Rickert

Publications and source records attributed to D E Rickert.

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Metabolism and excretion of dinitrobenzenes by male Fischer-344 rats.

All three dinitrobenzene (DNB) isomers cause methemoglobinemia, but only 1,3-DNB produces testicular toxicity in rats. In order to determine whether major differences exist in the routes of DNB metabolism, male Fischer-344 rats were given an oral dose (0.15 mmol/kg) of 14C-labeled 1,2-, 1,3-, or 1,4-DNB, and excreta were collected over 48 hr. Elimination of radiolabel was rapid; 85%, 60%, and 75% of the 1,2-, 1,3-, and 1,4-DNB dose was recovered in 24 hr, respectively. Urine was the primary route of excretion, accounting for 82% of the total dose of 1,2-DNB and 75% of the dose of 1,4-DNB after 48 hr. Radiolabel from 1,3-DNB was excreted to a slightly lesser extent in the urine (63% of the dose). A greater portion of radiolabel was excreted in the feces than with the other isomers (18% of total dose, compared to 8% and 9% with 1,2-DNB and 1,4-DNB, respectively). The major urinary metabolites of 1,2-DNB were S-(2-nitrophenyl)-N-acetylcysteine (42% of the dose), 2-nitroaniline-N-glucuronide (4%), 4-amino-3-nitrophenylsulfate (17%), 2-amino-3-nitrophenylsulfate (1.5%), and 2-(N-hydroxylamino)nitrobenzene (1-2%). The major urinary metabolites of 1,3-DNB were 3-aminoacetanilide (22%), 4-acetamidophenylsulfate (6%), 1,3-diacetamidobenzene (7%), and 3-nitroaniline-N-glucuronide (4%). The major metabolites of 1,4-DNB were 2-amino-5-nitrophenylsulfate (35%), S-(4-nitrophenyl)-N-acetylcysteine (13%), and 1,4-diacetamidobenzene (7%). These results suggest that the DNB isomers are primarily metabolized by nitro group reduction and conjugation with glutathione. The testicular toxicant 1,3-DNB was apparently metabolized exclusively by reduction.

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Metabolism of 2,4-dinitro[14C]toluene by freshly isolated Fischer-344 rat primary hepatocytes.

Fischer-344 rat hepatocytes display a capacity for both oxidation and reduction of 2,4-dinitrotoluene (2,4-DNT), a potent hepatocarcinogen. The major metabolite detected by high-pressure liquid chromatography was 2,4-dinitrobenzyl alcohol (2,4-DNBalc), which accounted for 75-80% of the total metabolites formed. The apparent KM and Vmax for 2,4-DNBalc formation was 58.0 microM and 25.5 nmoles/10(6) cells/30 min, respectively. Formation of 2,4-DNBalc was enhanced by treatment of rats with Aroclor 1254 (6-fold), phenobarbital (3.5-fold), and 3-methylcholanthrene (3.5-fold). In vitro additions of either SKF 525-A or 7,8-benzoflavone inhibited the formation of 2,4-DNBalc. Hepatocytes incubated under decreased oxygen concentrations (15%, 10%, 5% O2 in N2) displayed higher levels of reductive metabolism at 2,4-DNT (up to 5-fold) than when incubated in air. Concomitant decreases in oxidative metabolism of 2,4-DNT were observed in these experiments. Hepatocyte metabolism of 2-amino-4-nitrotoluene and 4-amino-2-nitrotoluene, two major products of rat cecal metabolism of 2,4-DNT, to 2-(N-acetyl)amino-4-nitrotoluene and 4-(N-acetyl)amino-2-nitrololuene, respectively, was observed. The results of this investigation suggest that hepatic reductive metabolism of 2,4-DNT probably plays a minor role in the overall metabolic scheme of 2,4-DNT.

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Metabolism and excretion of 2,4-dinitrotoluene in male and female Fischer 344 rats after different doses.

Female Fischer 344 rats are less susceptible to the hepatocarcinogenic effects of 2,4-dinitrotoluene (2,4-DNT) than males. This study is a comparison of the metabolism and excretion of 2,4-DNT in male and female rats after oral doses of 10, 35, or 100 mg of 14C-2,4-DNT per kg. The major route of elimination of 14C after all doses was the urine. 4-(N-Acetyl)amino-2-nitrobenzoic acid (4Ac2NBAcid), 2,4-dinitrobenzoic acid (2,4-DNMBAcid), 2-amino-4-nitrobenzoic acid (2A4NBAcid), and 2,4-dinitrobenzyl alcohol glucuronide (2,4-DNBAlcG) were identified in urine of rats. These four compounds accounted for greater than 85% of the radioactivity excreted in urine. Female rats excreted a significantly greater percentage of the dose in the urine as 2,4-DNBAlcG at doses of 10 or 35 mg/kg when compared to males. Both sexes showed dose-dependent changes in urinary excretion of 2,4-DNT metabolites. Males excreted a smaller percentage of the dose as 2,4-DNBAcid at 100 mg/kg than at 10 or 35 mg/kg. Females excreted less of the dose as 2,4-DNBAcid and 2,4-DNBAlcG at 100 mg/kg than at 10 or 35 mg/kg. The only sex difference in 2,4-DNT metabolism or excretion of sufficient magnitude to account for the sex difference in susceptibility to the hepatocarcinogenic effects of 2,4-DNT was the greater percentage of 2,4-DNT excreted as 2,4-DNBAlcG by female rats at 10 or 35 mg/kg.

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Metabolism of 2-methylnaphthalene in the rat in vivo. I. Identification of 2-naphthoylglycine.

Urine was collected from four female rats for 3 days after two subcutaneous injections with 0.3 mg of 2-methyl[8-14C]naphthalene per kg. Of the 14C injected, 55% was found in the urine. The urine was solvent-fractionated into a toluene fraction (4.9% of urine 14C), a chloroform fraction (11.7%), two ethyl acetate fractions (41.7%), and a methanol fraction (37.8%). Only about 3-5% of urine 14C appeared to be unchanged 2-methylnaphthalene. A major radioactive peak which was isolated from the chloroform fraction was further subdivided into three peaks by HPLC. These metabolites, which may be three isomeric dihydrodiols of 2-methylnaphthalene, represented 6-8% of urine 14C. The more polar fractions contained several radioactive peaks when examined by TLC. One of these peaks was hydrolyzed with base to glycine and a 14C-labeled material which was similar to 2-naphthoic acid by TLC and by HPLC. Mass spectrometry of this latter material and of the unhydrolyzed metabolite confirmed the presence of 2-naphthoic acid and 2-naphthoylglycine, respectively. In total, 2-naphthoylglycine accounted for 30-35% of urine 14C.

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PubMedDate not supplied

Metabolism and excretion of 2,6-dinitro [14C]toluene in vivo and in isolated perfused rat livers.

The metabolism and excretion of the hepatocarcinogen 2,6-dinitro-toluene (2,6-DNT) was investigated in Fischer-344 rats in vivo and in isolated perfused livers. Urinary excretion accounted for half of the dose (10 mg/kg) 72 hr after administration of 14C-2,6-DNT. 2,6-Dinitrobenzoic acid, 2,6-dinitrobenzyl alcohol glucuronide (2,6-DNBAlcGluc), and 2-amino-6-nitrobenzoic acid accounted for 95% of the urinary 14C. Fecal excretion accounted for one-fifth of the dose in 72 hr. 2,6-DNBAlcGluc was the major metabolite found in the perfusate and bile of isolated perfused rat livers. Biliary excretion of 2,6-DNBAlcGluc by livers from male rats was 3.3- and 8.6-fold that of female rats on perfusion with 20 and 70 microM 14C-2,6-DNT, respectively. No sex-dependent differences in biliary flow rates were observed. Twice as much 14C was found to be covalently bound to hepatic macromolecules in male than female rat livers in vivo. Decreased biliary excretion of 2,6-DNBAlcGluc may account for the lesser amount of 14C found to be covalently bound in female rat livers. Observations with 2,6-DNT parallel those made with 2,4-DNT, suggesting that both isomers are metabolized by the liver, excreted in the bile, deconjugated and further metabolized by the intestinal microflora, and transported back to the liver for, perhaps, additional metabolism and covalent binding to an endogenous component of the liver.

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Metabolism of nitrotoluenes by freshly isolated Fischer 344 rat hepatocytes.

2-Nitrotoluene (2NT), but not 3-nitrotoluene (3NT) or 4-nitrotoluene (4NT), is genotoxic in the in vivo-in vitro hepatic DNA repair assay. These differences in genotoxicity may be due to hepatic metabolism. For this reason, the metabolism of the nitrotoluenes was compared in hepatocytes isolated from male Fischer 344 rats. Hepatocytes were incubated with [U-14C]2NT, 3NT, or 4NT at concentrations from 25 to 1000 microM for up to 60 min. Metabolites were separated by reverse phase HPLC and identified by coelution with standards on HPLC, specific enzyme hydrolysis, and GC-MS analysis. 2NT was converted to 2-nitrobenzyl alcohol (52%), 2-nitrobenzyl alcohol glucuronide (28%), an unidentified metabolite (20%), and 2-nitrobenzoic acid (3%). Metabolites from 3NT were 3-nitrobenzoic acid (56%), 3-nitrobenzyl alcohol (29%), and 3-nitrobenzyl alcohol glucuronide (13%). 4NT was metabolized to S-(4-nitrobenzyl)glutathione (68%), 4-nitrobenzyl alcohol (12%), sulfate and glucuronide conjugates of 4-nitrobenzyl alcohol (6%), and 4-nitrobenzoic acid (2%) (expressed as percentage of total metabolism). The formation of the respective nitrobenzyl alcohols by hepatocytes was linear with respect to time for 15-20 min. The formation of other metabolites was linear over a 45-min incubation period. Incubation of 2NT, 3NT, or 4NT (1 mM) with rat hepatic microsomes produced only the respective nitrobenzyl alcohols and the rate of formation was linear for 90 min. The data suggest that each nitrotoluene isomer is metabolized to the corresponding benzyl alcohol, but that substantial differences in the metabolism of the benzyl alcohols exist.

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The metabolism and excretion of mononitrotoluenes by Fischer 344 rats.

The metabolism and excretion of 2-, 3-, and 4-nitrotoluene (2NT, 3NT, and 4NT, respectively) were studied in male Fischer 344 rats. Excreta were collected for 72 hr after an oral dose (200 mg/kg) of radiolabeled 2NT, 3NT, or 4NT. Radiolabel from each NT isomer was rapidly excreted (86, 73 and 74% of the dose for 2NT, 3NT, and 4NT, respectively in 24 hr). The urine was the major route of excretion with 70-85% of the dose being excreted by that route in 72 hr. Five to 13% and 0.0 to 0.1% of the dose was excreted in the feces and expired air, respectively, in 72 hr. The major metabolites excreted in urine in 72 hr after administration of 2NT were 2-nitrobenzoic acid (29% of the dose), an unidentified metabolite (16% of the dose), 2-nitrobenzyl glucuronide (14% of the dose), and S-(2-nitrobenzyl)-N-acetylcysteine (12% of the dose). The major metabolites excreted in urine in 72 hr after administration of 3NT were 3-nitrohippuric acid (24% of the dose), 3-nitrobenzoic acid (21% of the dose), and 3-acetamidobenzoic acid (12% of the dose). The major metabolites excreted in urine in 72 hr after administration of 4NT were 4-nitrobenzoic acid (28% of the dose), 4-acetamidobenzoic acid (27% of the dose), and 4-nitrohippuric acid (13% of the dose). Thus, the major urinary metabolites of 3NT and 4NT differed only quantitatively while those of 2NT were also qualitatively different.

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