Biomedical subjects

B I Ghanayem

Publications and source records attributed to B I Ghanayem.

At least 73 records · Page 4Linked to original sources

PubMed1987

Metabolic basis of ethylene glycol monobutyl ether (2-butoxyethanol) toxicity: role of alcohol and aldehyde dehydrogenases.

2-Butoxyethanol (BE) is a massively produced glycol ether of which more than 230 million pounds was produced in the United States in 1983. It is extensively used in aerosols and cleaning agents intended for household use. This creates a high potential for human exposure during its manufacturing and use. A single exposure of rats to BE causes severe hemolytic anemia accompanied by secondary hemoglobinuria as well as liver and kidney damage. Butoxyacetic acid (BAA) was earlier identified as a urinary metabolite of BE. In addition, we have recently identified two additional urinary metabolites of BE, namely, BE-glucuronide and BE-sulfate conjugates. The current studies were undertaken to investigate the metabolic basis of BE-induced hematotoxicity in male F344 rats. Treatment of rats with pyrazole (alcohol dehydrogenase inhibitor) protected rats against BE-induced hematotoxicity and inhibited BE metabolism to BAA. Pyrazole inhibition of BE metabolism to BAA was accompanied by increased BE metabolism to BE-glucuronide and BE-sulfate as determined by quantitative high-performance liquid chromatography analysis of BE metabolites in urine. There was approximately a 10-fold decrease in the ratio of BAA to BE-glucuronide + BE-sulfate in the urine of rats treated with pyrazole + BE compared to rats treated with BE alone. Pretreatment of rats with cyanamide (aldehyde dehydrogenase inhibitor) also significantly protected rats against BE-induced hematotoxicity and modified BE metabolism in a manner similar to that caused by pyrazole. Administration of equimolar doses of BE, the metabolic intermediate butoxyacetaldehyde, or the ultimate metabolite BAA caused similar hematotoxic effects. Cyanamide also protected rats against butoxyacetaldehyde-induced hematotoxicity. Further evidence of the involvement of metabolism in hematotoxicity was demonstrated by the administration of deuterium-labeled BE (1,1-dideuterio-2-BE) which resulted in a significant delay in the development of hematotoxicity. It is therefore concluded that: a) there is a strong correlation between the amount of BAA in the urine and BE-induced hematotoxicity; b) metabolic activation of BE via alcohol and aldehyde dehydrogenases is a prerequisite for the development of BE-induced hematotoxicity; and c) hematotoxicity induced by BE can be attributed to its metabolite BAA. Finally, the current studies may prove beneficial in the treatment of acute glycol ethers poisoning with alcohol dehydrogenase inhibitors.

Acetaldehyde↗

PubMed1986

Ethyl acrylate-induced gastric toxicity. III. Development and recovery of lesions.

Rats receiving 14 daily gavage doses of 100 or 200 mg/kg ethyl acrylate (EtAc) and killed at varying times following the end of dosing exhibited dose-dependent lesions and recovery from lesions in the forestomach. The glandular stomach which was previously shown to be affected by acute exposure to EtAc appeared to have adapted to resist EtAc toxicity with repeat exposure and appeared normal in all animals. Adaptation of the forestomach was characterized by increased papillomatous thickening with dose. Lesions observed in acute exposure to EtAc were still present with repeat dosing and were more pronounced at the high dose. Forestomachs of rats which received 100 mg/kg EtAc for 14 days were recovered to normal within 2 weeks following the last dose. Forestomachs of rats receiving 200 mg/kg EtAc still exhibited numerous lesions 2 weeks following the last dose, and mucosal hyperplasia was present in the forestomachs at 4 weeks postexposure. Two lesions, submucosal fibrosis and foreign body reaction, became more prevalent in high-dose animals with time. Foreign body reaction, which was present in all animals 4 weeks postexposure, appeared to have resulted from entrapment of hair and/or feed particles in forestomach lesions in the course of healing. It is speculated that the increased cell proliferation and the induced foreign body reactions may contribute to the previously demonstrated carcinogenic effect of EtAc on the rat forestomach.

Acrylates↗

PubMed1986

Association of chemically induced forestomach cell proliferation and carcinogenesis.

A number of chemicals have been shown to cause malignant neoplasms in the forestomach of Fischer 344 rats when administered chronically by gavage. The present study was designed to identify early forestomach lesions following 2-week repeated gavage administration of some of these forestomach carcinogens. In this manner, we attempted to examine the hypothesis that early cell proliferation is associated with repetitive gavage administration of these chemicals. Groups of 8 or more male F344 rats received 1 of 6 reported forestomach carcinogens (ethyl acrylate (EtAc), diglycidyl resorcinol ether(DGRE), 1,2-dibromoethane (DBE), 1,2-dibromo-3-chloro-propane (DBCP), 1-chloro-2-methylpropene (dimethylvinyl chloride, DMVC) and 3-chloro-2-methylpropene (CMP)), 1 of 2 structurally related chemicals (methyl methacrylate (MMA) and dichloroethane (DCE)) which were negative in chronic carcinogenicity studies or the vehicle (corn oil) alone 5 days/week for 2 weeks. Histopathologic examination of forestomachs of rats killed 24 h after the last dose indicated no significant difference in the incidence or severity of epithelial cell proliferation in the rat forestomach between the vehicle control group and the 2 negative control groups. In contrast, the incidence and severity of epithelial cell proliferation of the rat forestomach in every group treated with a forestomach carcinogen was significantly higher than the incidence in the vehicle or negative control groups. These results suggest that early epithelial cell proliferation of the forestomach may be associated with at least some chemicals that induce forestomach neoplasia following chronic administration by gavage.

Animals↗

PubMed1986

Prevention of acrylonitrile-induced gastrointestinal bleeding by sulfhydryl compounds, atropine and cimetidine.

We have recently demonstrated that acrylonitrile (VCN) causes acute gastric hemorrhage and mucosal erosions. The current studies were undertaken to investigate the effects of the sulfhydryl-containing compounds, cysteine and cysteamine, the cholinergic blocking agent atropine and the histamine H2 receptor antagonist, cimetidine on the VCN-induced gastrointestinal (GI) bleeding in rats. Our data shows that pretreatment with L-cysteine, cysteamine, atropine or cimetidine has significantly protected rats against the VCN-induced GI bleeding. A possible mechanism of the VCN-induced GI bleeding may involve the interaction of VCN with critical sulfhydryl groups that, in turn, causes alteration of acetylcholine muscarinic receptors to lead to gastric hemorrhagic lesions and bleeding.

Acrylonitrile↗

PubMed1985

Ethyl acrylate-induced gastric toxicity. I. Effect of single and repetitive dosing.

Ethyl acrylate (EtAc) is widely used in the production of polymers and copolymers for use in the preparation of latex paints, textiles, paper coatings, and specialty plastics. EtAc caused squamous cell carcinomas and papillomas in the forestomach (nonglandular portion of the stomach) of both sexes of F344 rats and B6C3F1 mice when administered chronically by gavage. The current studies were undertaken to investigate and characterize the nature of the acute gastric toxicity caused by EtAc. Gavage administration of a single dose of 100, 200, or 400 mg/kg EtAc (in corn oil) to F344 male rats caused dose-and time-dependent mucosal and submucosal edema and vacuolization of the tunica muscularis in the forestomach and mild submucosal edema in the glandular stomach. Equivalent sc or ip doses did not produce similar gastric lesions. Treatment of rats with two or four consecutive oral daily doses (200 mg/kg each) of EtAc caused mucosal edema associated with vesicle formation, mucosal hyperplasia, submucosal edema and inflammation, and vacuolization of the tunica muscularis of the forestomach. Submucosal edema and inflammation were also observed in the glandular stomach and mucosal erosions or ulcers were observed in both portions of the stomach after repeated oral exposure to EtAc. The absence of systemic toxicity plus the dependency of gastric lesions on the gavage route of administration suggest that the EtAc-induced gastric lesions may be a consequence of localized hemodynamic changes, specifically those characteristic of a classical immediate inflammatory response to an injurious agent at the site of administration.

Acrylates↗

PubMed1985

Ethyl acrylate-induced gastric toxicity. II. Structure-toxicity relationships and mechanism.

Earlier studies conducted in this laboratory demonstrated that gavage administration of ethyl acrylate caused pronounced gastric toxicity in rats given single or repeated doses. The current studies were undertaken to investigate the structural, metabolic, and physical basis of this chemically induced gastric toxicity. Gavage administration of equimolar doses (2 mmol/kg) of methyl or ethyl acrylate in corn oil resulted in profound gastric toxicity in male F344 rats, while acrylic acid and n-butyl acrylate were without effect. Furthermore, gavage administration of equimolar doses of methyl propionate or ethyl propionate (saturated analogues of methyl acrylate and ethyl acrylate, respectively) as well as methacrylic acid esters were without gastric toxicity. These results indicate that structural requirements for acrylate esters to cause gastric lesions include an intact ester moiety, a double bond, and no substitution at carbon number 2. Additional studies indicate that gastric toxicity may be attributed to the intact ester molecule or to metabolite(s) other than products of carboxylesterase-mediated hydrolysis (acrylic acid and alcohol) and that gastric toxicity is dependent upon both acrylate ester concentration in dose vehicle and the lipophilicity of the dose vehicle (corn oil vs water).

Acrylates↗

PubMed1985

Acrylonitrile-induced gastric mucosal necrosis: role of gastric glutathione.

Acrylonitrile [vinyl cyanide (VCN)] induces acute hemorrhagic focal superficial gastric mucosal necrosis or gastric erosions. In this report the authors have studied the mechanism of the VCN-induced gastric erosions. VCN-induced gastric lesions are coupled with a marked decrease of gastric reduced glutathione (GSH) concentration. Pretreatment of rats with various metabolic modulators (cytochrome P-450 monooxygenase and GSH) before VCN demonstrated that there is an inverse and highly significant correlation between gastric GSH concentration and the VCN-induced gastric erosions. Pretreatment of rats with sulfhydryl-containing compounds protected against the VCN-induced gastric necrosis and blocked the VCN-induced gastric GSH depletion. Furthermore, pretreatment of rats with atropine, which blocks muscarinic receptors, protected rats against the VCN-induced gastric erosions. The working hypothesis is that depletion and/or inactivation of critical endogenous sulfhydryl groups causes configurational changes of cholinergic receptors and increases agonist binding affinity, which, among other actions, leads to the causation of gastric mucosal erosions.

Acrylonitrile↗

PubMed1984

Acetyl salicylic acid-induced gastric mucosal lesions: no role of gastric glutathione.

Gastric glutathione (GSH) depletion has been implicated in the causation of gastric mucosal lesions by ethanol, diethylmaleate (DEM) and acrylonitrile (VCN). The purpose of the current studies was to investigate the role of gastric GSH in Acetyl Salicylic acid (Aspirin; ASA) induced gastric lesions. Intragastric administration of doses of ASA to rats, which caused gastric mucosal lesions, had no significant influence on gastric or hepatic GSH concentrations. Furthermore, pretreatment of rats with sulfhydryl-containing chemicals (e.g. L-cysteine) failed to protect against the ASA- or Acid-induced gastric lesions. Our findings indicate that gastric GSH plays no role in the pathogenesis of ASA-induced gastric mucosal necrosis.

Animals↗

PubMed1983

Acrylonitrile-induced gastrointestinal hemorrhage and the effects of metabolism modulation in rats.

Acrylonitrile (VCN) is a heavily used monomer in plastic and fiber industries. Quantitatively, VCN-induced gastrointestinal hemorrhage is time and dose dependent and is not the result of a direct irritating action of VCN on gastric tissues. The effect of cytochrome P-450 enzymes inducers was studied. Pretreatment with phenobarbital decreased the VCN-induced GI blood loss (55%), while Aroclor 1254 drastically increased it (240%). VCN administration to rats treated with cobalt chloride or SKF 525A (cytochrome P-450 enzymes inhibitors) resulted in a significant protection against GI bleeding (10 and 40%, respectively). Treatment with diethylmaleate (a known depletor of reduced glutathione) prior to VCN administration, produced no significant change in the VCN-induced GI bleeding. Potassium cyanide (KCN) administration to rats failed to produce significant GI bleeding. These results indicate that metabolic activation of the VCN molecule, to a metabolite(s) other than cyanide by the cytochrome P-450 enzymes, is a prerequisite for VCN to induce gastric hemorrhage.

Acrylonitrile↗

PubMed1982

In vivo biotransformation and biliary excretion of 1-14C-acrylonitrile in rats.

1-14C-Acrylonitrile (VCN) was give orally to rats, 27% of the given dose was excreted in bile in 6 h. When 1-14C-VCN was given to overnight fasted or cobaltous chloride treated rats, a significant increase in the biliary excretion occurred. Pretreatment of rats with phenobarbital produced no change, while diethyl maleate pretreatment significantly decreased the portion of the dose excreted in bile in 6 h. Four metabolites of 1-14C-VCN have been isolated from the collected bile, and characterized. The two major biliary metabolites were found to be glutathione (GSH) conjugates of VCN, indicating the importance of GSH in VCN biotransformation.

Acrylonitrile↗

PubMed1982

Quantitative determination of gastrointestinal bleeding in rats.

A method for the quantitative determination of gastrointestinal bleeding in rats is described. The method is dependent upon the extraction of blood from stomach and intestinal contents, or from feces, of rats. The blood (heme) in the dry extract is measured spectrophotometrically after conversion to pyridine-hemochromogen. The heme concentration is computed from the spectrophotometric scans of the dithionate-reduced versus the oxidized pyridine hemochromogen. The current method is suitable for the quantitative determination of acute and chronic gastrointestinal blood loss. It is also experimentally useful as a pharmacological screening technique and for quantitative comparisons of drug-induced gastrointestinal bleeding. Contrary to existing methods, this method is easier, reproducible, accurate, less expensive, less time consuming, less risky (no radioactive material is required), useful in providing some information about the site of gastrointestinal bleeding, and is not influenced by changes in bile formation and flow.

Animals↗

PubMedDate not supplied

Assessment of the acute acrylonitrile-induced neurotoxicity in rats.

Acrylonitrile (VCN) is an aliphatic nitrile which is used extensively in manufacturing of synthetic fibers, plastics, and rubber. Although the neurotoxicity of VCN is recognized, no thorough characterization of this effect has been reported. Current studies were designed to quantitatively characterize the acute phase of VCN-induced cholinomimetic neurotoxicity, and to determine the effects of dose, route of administration, and atropine on such toxicity. Administration of a single gavage or subcutaneous doses of 20, 40, or 80 mg VCN/kg to male Sprague-Dawley rats causes two distinctive phases of acute neurotoxic effects. Signs observed in the early phase had a rapid onset, and were cholinomimetic in nature. They included salivation, lacrimation, chromodacryorrhea, polyuria, miosis, vasodilatation in face, ears and extremities, increased gastric secretion, and diarrhea. A late phase developed hours after VCN dosing, and the toxic signs included depression, convulsions, and respiratory failure followed by death at high doses. These results revealed that the cholinomimetic toxicity induced by VCN was dose related regardless of the route of administration. In another study, rats were pretreated with atropine (1 mg/kg, IP) prior to VCN (40 mg/kg) in order to investigate the role of the cholinergic system. Atropine protected rats against VCN-induced cholinomimetic neurotoxicity, suggesting possible involvement of the cholinergic system. Finally, this work provides essential basic information for studying the biochemical, pharmacological, and neurological basis of VCN-induced neurotoxicity in the rat.

Acrylonitrile↗

PubMedDate not supplied

Dental pulp infarction in female rats following inhalation exposure to 2-butoxyethanol.

Female Fischer 344 (F344)/N rats (10 per exposure group) were exposed to 2-butoxyethanol (BE) vapors (0, 31, 62.5, 125, 250, or 500 ppm 6 h/d, 5 d/wk, for 13 weeks) to characterize its prechronic toxicity. Dental lesions consisting of bilateral multifocal dental pulp thrombosis, pulp infarction, and odontoblast infarction were noted in the maxillary incisors of 3 of 4 rats from the 500-ppm group that were sacrificed when moribund during the first week of exposure. In addition, 1 rat from the 500-ppm group that was sacrificed on day 32 had similar unilateral incisor lesions but with additional findings consistent with a unilateral maxillary incisor fracture. In contrast, rats sacrificed after 13 weeks of exposure lacked dental lesions. In conclusion, BE has the potential to cause pulp thrombosis and odontoblast infarction in female rats. The apparent variability in response to BE noted in moribund sacrificed vs terminally sacrificed rats was attributed to development of tolerance to BE-induced hemolysis and subsequent incisor regeneration.

Administration, Inhalation↗

PubMedDate not supplied

Using cytochrome P-450 gene knock-out mice to study chemical metabolism, toxicity, and carcinogenicity.

Cytochrome P-450 (CYP) enzymes are heme-containing proteins that carry out oxidative metabolism of a wide range of structurally diverse exogenous chemicals and therapeutic agents as well as endogenous compounds. For some of these xenobiotics, oxidative metabolism results in the formation of toxic, mutagenic, or carcinogenic metabolites. In the past, the role of CYP enzymes in metabolism and chemical-induced toxicity was studied indirectly through use of specific antibodies or inducers and inhibitors of these enzymes. Progress in molecular biology and the ability to bioengineer animal models that do not express CYP1A2, CYP1A1, CYP1B1, CYP2E1, or both CYP1A2 and CYP2E1 isozymes has allowed for direct investigations of the in vivo role of these enzymes in the metabolism, toxicity, and carcinogenicity of xenobiotics. This article reviews research conducted to date that utilizes these genetically bioengineered mice in metabolism, toxicity, or carcinogenicity studies of chemicals. Some studies showed a positive correlation between in vivo results and in vitro predictions for the role of a specific CYP in chemical-induced effects, whereas other studies did not support in vitro predictions. Work reviewed herein demonstrates the importance of using animal models for investigating the role of specific CYP enzymes in metabolism and chemical-induced toxicity or carcinogenicity rather than relying solely on in vitro techniques. Eventually, studies of this nature will facilitate a more accurate assessment of human risks with regard to chemicals by helping us to understand the relationships between chemical metabolism, carcinogenicity, and polymorphisms in CYP enzymes.

Animals↗

PubMedDate not supplied

Demonstration of a temporal relationship between ethyl acrylate-induced forestomach cell proliferation and carcinogenicity.

Ethyl acrylate (EA) is a known forestomach carcinogen in both rats and mice. Recent work in this laboratory indicated that carcinogenic doses of EA administered by gavage for 13 wk resulted in a sustained increase in forestomach epithelial hyperplasia as long as exposure to EA continued. However, hyperplasia regressed and no forestomach neoplasms were seen after a 19-mo recovery period. Current studies were designed to further investigate the time required for sustained hyperplasia to lead to neoplasia as well as the organ specificity of EA-induced cell proliferation/hyperplasia vs carcinogenicity. EA was administered at 200 mg/kg (po) to male Fischer-344 rats, 5 days/wk. Squamous cell proliferation/hyperplasia was observed in the forestomach of all rats that received EA for 6 or 12 mo. Treatment of rats with EA for 12 mo followed by 2 mo of recovery resulted in the development of forestomach papillomas in 2 of 5 treated rats. Furthermore, animals treated for 12 mo and allowed 9 mo of recovery exhibited an increase in forestomach squamous cell carcinomas and papillomas at a combined incidence of 4 in 13. In contrast, animals treated with EA for 6 mo and allowed 2 or 15 mo of recovery exhibited a time-dependent regression of cell proliferation and did not develop forestomach neoplasms. No significant elevation in liver cell proliferation or neoplasia was seen at any time in any of the rats included in the present study, further confirming the organ specificity in the relationship between EA-induced cell proliferation and carcinogenicity. In conclusion, EA resulted in increased cell proliferation in the target organ of carcinogenicity (forestomach) but not in nontarget organs such as the liver. This work indicates that cell proliferation, sustained for a sufficient period of time, results in the development of neoplasia despite cessation of chemical administration. Furthermore, a temporal relationship exists between EA-induced epithelial cell proliferation and forestomach carcinogenicity.

Acrylates↗

PubMedDate not supplied

Disseminated thrombosis and bone infarction in female rats following inhalation exposure to 2-butoxyethanol.

Groups of 10 male and 10 female F344/N rats were exposed to 0, 31, 62.5, 125, 250, and 500 ppm of 2-butoxyethanol (BE) by inhalation, 6 hr/day, 5 days/wk, for 13 wk. Four moribund female rats from the 500 ppm group were sacrificed during the first 4 days of exposure, and 1 moribund female from the same group was sacrificed during week 5. Dark irregular mottling and/or loss of the distal tail were noted in sacrificed moribund rats. Similar gross lesions were noted in the terminally sacrificed females exposed to 500 ppm BE. Histologic changes noted in the day 4 sacrificed moribund rats included disseminated thrombosis involving the coccygeal vertebrae, cardiac atrium, lungs, liver, pulp of the incisor teeth, and the submucosa of the anterior section of the nasal cavity. Alterations noted in coccygeal vertebrae from the 500 ppm sacrificed moribund rats included ischemic necrosis and/or degeneration of bone marrow cells, bone-lining cells, osteocytes (within cortical and trabecular bone), and chondrocytes (both articular and growth plate), changes that are consistent with an infarction process. The moribund female rat that was sacrificed during week 5 and those female rats treated with 500 ppm and sacrificed following 13 wk of treatment lacked thrombi, but they had coccygeal vertebral changes consistent with prior infarction and transient or complete bone growth arrest. No bone lesions or thrombi were noted in the male rats treated with the same doses of BE. In conclusion, exposure to 500 ppm BE vapors caused acute disseminated thrombosis and bone infarction in female rats. Possible pathogenic mechanisms are discussed.

Administration, Inhalation↗

PubMedDate not supplied

Effects of dose, strain, and dosing vehicle on methacrylonitrile disposition in rats and identification of a novel-exhaled metabolite.

Methacrylonitrile (MAN), an aliphatic nitrile used in the production of plastics and elastomers, is structurally related to the known animal carcinogen, acrylonitrile. Although MAN has potential to cause significant toxicity, minimal information is available on its toxicity or fate. Current studies were designed to investigate the biological fate of [2-14C]MAN in male F344 rats. Following gavage administration of 115, 11.5, or 1.15 mg MAN/kg in water, male F344 rats were placed in glass metabolism cages and urine, expired air, and feces were collected. Rats were sacrificed at various times, and the concentration of MAN-derived radioactivity in tissues was determined. MAN was rapidly absorbed from the gastrointestinal tract and distributed to all major tissues. After gavage administration of 1.15-115 mg/kg, [2-14C]MAN is primarily eliminated in the expired air. Sixty to 70% of the low and medium doses were exhaled as 14CO2 in 72 hr compared with 25% of the highest dose. Whereas 40% of the high dose was expired as organic volatiles in 72 hr, only 9-12% of the low and medium doses were exhaled as such. It is therefore apparent that saturation of MAN metabolism occurs at the high dose. HPLC analysis of expired organic volatiles from MAN-treated rats showed that it contained two components that were identified as unchanged MAN and acetone. The MAN:acetone ratio was directly proportional to dose and decreased as a function of time. Urinary excretion accounted for 20-30% of all MAN doses within 72 hr after dosing. Investigating the effect of dosing vehicle on MAN disposition in rats revealed that administration of 115 mg MAN/kg in oil resulted in the death of rats within 24 hr after treatment. Furthermore, monitoring the fate of MAN in these rats before death showed that a significantly higher percentage of the dose was eliminated in urine and expired air. Analysis of this expired air also revealed that significantly more acetone and less unchanged MAN were exhaled by these animals. It is apparent that administration of MAN to F344 rats in oil resulted in slower absorption, decreased elimination of unchanged MAN, and increased metabolism to acetone and/or decreased degradation of acetone to CO2. The combination of these effects of an oil vehicle may have contributed to the death of rats by MAN. Comparison of the metabolism and disposition of MAN in F344 and Sprague-Dawley rats showed minor differences between the two strains.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMedDate not supplied

Comparative metabolism and disposition of 1-chloro- and 3-chloro-2-methylpropene in rats and mice.

A recent 2-year carcinogenicity study found that gavage administration of 3-chloro-2-methylpropene (CMP), containing 5% 1-chloro-2-methylpropene (dimethylvinyl chloride, DMVC), caused forestomach neoplasms in rats and mice. Similar chronic studies revealed that DMVC caused forestomach neoplasms in both rats and mice; neoplasms of the nasal and oral cavities were observed in rats but not in mice. In the current studies we have investigated the metabolic basis of these differences. Daily doses of 150 mg/kg of 2-[14C]DMVC or 2-[14C]CMP were administered to rats for 1, 2, or 4 consecutive days. One daily dose of 150 mg/kg of DMVC was administered to mice. Both DMVC and CMP were rapidly metabolized; however, CMP was cleared at a slightly lower rate. Rats exhaled approximately 25 and 10% of the DMVC and CMP as CO2, respectively. Mice exhaled 25% of the DMVC as CO2. Rats expired 30% of the administered DMVC unchanged in the 24 hr after dosing compared to only 7% of the administered CMP. Mice expired 5% of the administered DMVC in the same time period. This observation may explain the occurrence of tumors in the nasal and oral cavities of rats treated with DMVC but not in rats treated with CMP or in mice treated with DMVC in 2-year carcinogenicity studies. The 24-hr urinary excretion in rats was 35% of the administered DMVC compared to 58% of CMP. Mice excreted 47% of the administered DMVC in 24 hr in the urine. An unusual urinary metabolite of DMVC, 2-amino-6-methyl-4-thia-5-heptene-1,7-dioic acid, was identified.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylation↗