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M R Boyd

Publications and source records attributed to M R Boyd.

At least 253 records · Page 14Linked to original sources
PubMed1983

Nephrotoxicity of semustine.

Semustine is an investigational cancer chemotherapeutic agent in widespread use. This agent has now been documented to produce nephrotoxicity and renal failure with long-term administration. We collected 29 cases of semustine nephrotoxicity from the literature and six unpublished cases brought to the attention of the National Cancer Institute. Using these 35 cases as a data base, we have analyzed the incidence, dose and treatment duration relationships, clinical and histologic manifestations, and clinical course of semustine nephrotoxicity. In addition, we discuss the possible mechanisms of this nephrotoxicity based upon ongoing laboratory work. We conclude that there is a high risk of severe nephrotoxicity from semustine when the cumulative dose exceeds 1200 mg/m2 and that there may be considerable delay in onset of the renal dysfunction.

Animals↗
PubMed1983

Nephrotoxicity of 1-(2-chloroethyl)-3-(trans-4-methylcyclohexyl)-1-nitrosourea (MeCCNU) in the Fischer 344 rat.

A single s.c. injection of 1-(2-chloroethyl)-3-(trans-4-methylcyclohexyl)-1-nitrosourea (MeCCNU; 20-140 mg/kg) resulted in rapid decreases in renal function as well as leading to a chronic progressive nephropathy in male Fischer 344 rats. Disturbances in renal function were proportional to the dose of MeCCNU administered and included impaired tubular transport of p-aminohippuric acid, a decrease in urine concentrating ability, an increase in urine pH, polyuria, proteinuria and enzymuria. The tubular accumulation of p-aminohippuric acid by kidney slices was decreased as early as 1 hr after MeCCNU administration (100 mg/kg), was maximal within 12 hr and remained depressed for at least 28 days after a single injection of either 40 or 80 mg/kg. Changes in other measures of renal function (increased lactate dehydrogenase excretion, alkalinuria and decreased urine concentrating ability) were delayed from 1 to 6 days after MeCCNU administration and in some cases progressed in severity throughout the 28-day duration of the experiment. The delay between the first evidence of renal damage (decreased p-aminohippuric acid uptake) and the subsequent appearance of enzymuria, proteinuria, polyuria and alkalinuria appears to correspond to a similar delay between the initial insult and the eventual development of cellular necrosis and other histopathological changes. These results demonstrate that MeCCNU is a nephrotoxicant in rats and indicate that even a single acute dose may lead to chronic and irreversible effects on the kidney. The in vivo toxicity model defined herein appears to be an appropriate one for further study of the mechanism of nephrotoxicity of MeCCNU.

Animals↗
PubMed1983

Covalent binding of metabolites of 4-ipomeanol to rabbit pulmonary and hepatic microsomal proteins and to the enzymes of the pulmonary cytochrome P-450-dependent monooxygenase system.

The covalent binding of metabolites of 4-ipomeanol, a potent lung toxin, to proteins in rabbit pulmonary and hepatic microsomal preparations and in purified monooxygenase systems was investigated. The rate of binding was 12-fold greater in pulmonary preparations than in hepatic preparations. Covalent binding in pulmonary microsomal fractions was inhibited 39 to 49% by antibodies to rabbit pulmonary cytochrome P-450II or P-450I and 90% by antibodies to cytochrome P-450 reductase. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis and scintillation autoradiography of pulmonary microsomal proteins revealed the presence of heavily labeled bands throughout the molecular weight range (Mr) examined. Two of these bands corresponded in mobility to pulmonary cytochrome P-450I (Mr 52,000) and P-450II (Mr 58,000). In addition, there was a great deal of binding associated with very high molecular weight proteins, probably in the form of cross-linked aggregates which were unable to penetrate the gel matrix. In the absence of cofactor, no binding was observed. Binding was decreased by the addition of the following: antireductase greater than glutathione = NADH (without NADPH) greater than anti-II greater than anti-I. The electrophoretic patterns of the proteins from incubation of [3H]-4-ipomeanol with purified pulmonary P-450-dependent monooxygenase enzymes were also examined. In the complete system, the majority of the binding was associated with high molecular weight species located at the origin and with low molecular weight species that migrated with the tracking dye. In the absence of cofactor, some binding to proteins that corresponded with cytochrome P-450 and P-450 reductase was observed. Protease digestion of incubation mixtures resulted in the migration of all bound material at the dye front.

Animals↗
PubMed1982

Effects of phenobarbital and 3-methylcholanthrene on the in vivo distribution, metabolism and covalent binding of 4-ipomeanol in the rat; implications for target organ toxicity.

The effects of phenobarbital (PB) and 3-methylcholanthrene (MC) on the distribution, metabolism and covalent binding of 4-ipomeanol were examined in the rat. An analysis of tissue extracts by high-pressure liquid chromatography (HPLC) showed that both treatments markedly decreased the concentrations of unmetabolized 4-ipomeanol at all times examined. PB treatment increased the urinary excretion of nonbound 4-ipomeanol metabolites, while MC treatment did not alter their excretion. Analysis of urine by HPLC indicated that the increased concentration of urinary metabolites found in the phenobarbital-treated rats was attributable primarily to an increased excretion of ipomeanol-4-glucuronide. These data indicate that the decreased pulmonary covalent binding and lethality of 4-ipomeanol in the rat after MC and PB were caused by alterations in the tissue distribution of the parent compound. Pulmonary concentrations of unmetabolized 4-ipomeanol were decreased by MC through an increased metabolism of 4-ipomeanol in the liver, primarily to toxic products that bind covalently in that tissue and lead to hepatoxicity. PB produced a similar decrease in unmetabolized 4-ipomeanol concentrations in lung but by an enhanced in vivo metabolism and clearance of 4-ipomeanol, primarily through a "nontoxic" pathway, glucuronidation, and did not lead to hepatotoxicity.

Animals↗
PubMed1982

Protective role of endogenous pulmonary glutathione and other sulfhydryl compounds against lung damage by alkylating agents. Investigations with 4-ipomeanol in the rat.

Because endogenous glutathione is known to participate in the detoxification of highly reactive, hepatotoxic drug metabolites, we studied the role of this substance in the pulmonary toxicity of 4-ipomeanol [1-(3-furyl)-4-hydroxypentanone] in rats. 4-Ipomeanol was an appropriate model for these studies since previous investigations have indicated that an alkylating metabolite, formed in situ, is responsible for selective lung damage by 4-ipomeanol. Toxic doses of 4-ipomeanol preferentially depleted rat lung glutathione. Pretreatment of animals with piperonyl butoxide, an inhibitor of the metabolic activation of 4-ipomeanol, prevented both the depletion of lung glutathione and the pulmonary toxicity of 4-ipomeanol. Prior depletion of lung glutathione by diethylmaleate increased both the pulmonary covalent binding and the toxicity of 4-ipomeanol, whereas administration of cysteine and cysteamine decreased both the covalent binding and the toxicity. These in vivo studies, in conjunction with previous in vitro studies which showed inhibitory effects of sulfhydryl compounds on the covalent binding of 4-ipomeanol, are consistent with the view that pulmonary glutathione plays a protective role against pulmonary alkylation and lung toxicity by 4-ipomeanol, probably by reacting with the toxic metabolite(s) to form nontoxic conjugate(s). Pulmonary glutathione may similarly provide protection against other electrophilic drugs or metabolites that can damage the lungs.

Animals↗
PubMed1982

Distribution and metabolism of the pulmonary alkylating agent and cytotoxin, 4-ipomeanol, in control and diethylmaleate-treated rats.

Diethylmaleate (DEM), an agent which depletes tissue glutathione (GSH), increased the covalent binding and toxicity of 4-ipomeanol [1-(3-furyl)-4-hydroxypentanone] in rats. The distribution of unmetabolized 4-ipomeanol-[5-14C] and its metabolites were studied in tissue extracts by high-pressure liquid chromatography (HPLC) in control and DEM-treated rats. At all time periods examined, DEM treatment produced no significant effect on the tissue distribution of unchanged 4-ipomeanol. In both groups, the relative tissue concentrations of unmetabolized 4-ipomeanol were in the order blood greater than lung greater than liver. In control rats, the relative tissue concentrations of nonbound, solvent-extractable 4-ipomeanol metabolites (hereafter referred to simply as "4-ipomeanol metabolites"), as well as the covalently bound 4-ipomeanol metabolites (hereafter referred to as "covalently bound 4-ipomeanol equivalents" to distinguish from all other metabolites) were in the order lung greater than liver greater than blood. The pulmonary levels of both the covalently bound 4-ipomeanol equivalents and the 4-ipomeanol metabolites were increased markedly by DEM treatment at all time periods examined. The total pool of urinary 4-ipomeanol metabolites was significantly decreased by DEM treatment, but the total amounts of excreted ipomeanol-4-glucuronide, the major metabolite of 4-ipomeanol in rats, were not significantly different in the control and DEM-treated rats. These data are consistent with the view that the increased pulmonary covalent binding and toxicity of 4-ipomeanol produced by diethylmaleate treatment in rats are due to the depletion of pulmonary GSH by the DEM and not a major DEM-induced alteration in the tissue distribution of the parent 4-ipomeanol.

Animals↗
PubMed1982

In vitro metabolic activation of the pulmonary toxin, 4-ipomeanol, in nonciliated bronchiolar epithelial (Clara) and alveolar type II cells isolated from rabbit lung.

The metabolism and covalent binding of 4-ipomeanol (IPO), a pulmonary toxin, were investigated in pulmonary cells isolated from rabbit. 3H-labeled IPO was incubated with freshly, isolated, intact alveolar type II cells (83% purity), nonciliated bronchiolar epithelial (Clara) cells (77% purity) and alveolar macrophages (greater than 90% purity). Covalent binding of radioactive material to type II and Clara cells was observed by autoradiography and by a biochemical method. IPO binding to cells was almost totally prevented by 1 mM piperonyl butoxide, an inhibitor of the cytochrome P-450-dependent metabolism of IPO. No covalent binding was observed with alveolar macrophages in the presence or absence of piperonyl butoxide. The maximal rates of enzyme-mediated covalent binding of IPO to protein were greater in the Clara cells (135 pmol/10(6) cells/min) than in the type II cells (13 pmol/10(6) cells/min). Incubation of either sonicated Clara or type II cell fractions with [3H]IPO, glutathione and NADPH (20 min, 37 degrees C) resulted in the formation of two distinct radiolabeled glutathione conjugates.

Animals↗
PubMed1982

The relationship between the catalytic activities of rabbit pulmonary cytochrome P-450 isozymes and the lung-specific toxicity of the furan derivative, 4-ipomeanol.

Metabolism of the pulmonary toxin, 4-ipomeanol, in microsomal preparations from rabbit liver and lung and in purified cytochrome P-450-dependent monooxygenase systems was investigated. The rate of formation of reactive electrophilic products from 4-ipomeanol was estimated by measuring covalent binding to protein or glutathione. Pulmonary microsomal preparations were much more active than hepatic preparations in mediating these reactions. Both of the rabbit pulmonary cytochrome P-450 isozymes, P-450I and P-450II, were active in the metabolism of 4-ipomeanol. In the assay for covalent binding to protein, P-450I was slightly more active than P-450II at high substrate concentrations and significantly more active at low substrate concentrations. Incubation of either isozyme with 4-ipomeanol produced two glutathione conjugates but at quite different ratios. Rates of metabolism determined by conjugate formation in the purified systems were about 3 times the rates determined by covalent binding to protein, whereas both determinations gave the same values in the microsomal preparations. The relationship between the activities of P-450I and P-450II in the metabolism of 4-ipomeanol and the pulmonary toxicity of 4-ipomeanol is discussed.

Animals↗
PubMed1981

Renal toxicity due to reactive metabolites formed in situ in the kidney: investigations with 4-ipomeanol in the mouse.

The in vitro metabolism and covalent binding of the furan derivative, 4-ipomeanol, was mediated by oxygen-requiring, NADPH-dependent, CO-inhibitable microsomal enzymes present in the livers, lungs and kidneys of adult male mice. These activities were inhibitable by piperonyl butoxide and they were markedly enhanced in hepatic microsomes from C57/6J mice, but not DBA/2J mice, pretreated with 3-methylcholanthrene. The i.p. administration of 4-ipomeanol to adult male mice resulted in the covalent binding of large amounts of its metabolite(s) in the lungs and kidneys. The material bound in the kidneys was located predominantly in the proximal renal cortical tubules. The covalent binding and toxicity of 4-ipomeanol to the renal tubules could be prevented by pretreatment of the animals with piperonyl butoxide. The hepatic covalent binding and toxicity of 4-ipomeanol were enhanced and the pulmonary and renal covalent binding and toxicity were decreased in C57BL/6J mice pretreated with 3-methylcholanthrene; however, this pretreatment did not significantly alter the tissue covalent binding or toxicity of 4-ipomeanol in noninducible DBA/2J mice. These results support the view that renal damage by 4-ipomeanol in the mouse is caused by reactive 4-ipomeanol metabolite(s) formed in situ in the kidney.

Animals↗
PubMed1981

Toxicity mediated by reactive metabolites of furans.

Furan derivatives occur widely in the environment, and several of these compounds cause necrosis of target cells within certain organs, including the liver, the kidneys, and the lungs. The tissue specificity may vary from compound to compound. For individual compounds, the specificity may be greatly influenced by the species, sex, and age of the test animal and by the prior exposure of the animal to inducers of drug metabolism. Studies in vitro and in vivo indicate that cytochrome P-450 enzymes in the target tissues mediate the formation of highly reactive, electrophilic furan metabolites that bind covalently to tissue macromolecules. Epoxides are suspected, but not proven, to be the proximate or ultimate toxic metabolites of furans. One study suggested that epoxide hydratase might influence the covalent binding of a furan derivative in vitro, but similar investigations with other furans have been negative. Glutathione (GSH) can inhibit the covalent binding of reactive furan metabolites in vitro, presumably by forming less reactive, water-soluble conjugates with the activated furans. GSH-furan conjugate formation can occur nonenzymatically, and a study with 4-ipomeanol indicated that cytosolic enzyme preparations did not enhance the amounts of conjugates produced. It is likely that GSH provides a major mechanism for detoxification of some furans in vivo.

Animals↗