Biomedical subjects
Publications and source records attributed to M R Boyd.
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When a compound that is removed from the body by metabolism produces toxicity in extrahepatic organs directly, rather than via active metabolites, induction or inhibition of the drug-metabolizing enzymes simply will decrease or enhance, respectively, the toxic effects of the compound. On the other hand, the effects of chemicals whose toxicity depends on their activation by metabolism may be modified in a complex way by pretreatment with inducers or inhibitors of the enzymes; it may, therefore, be impossible to predict the effect of pretreatment on the metabolism and toxicity of a given compound. The major sources of such complexity are that (a) inducers and inhibitors can have multiple effects on pathways of drug toxification or detoxification, both in the liver and in extrahepatic tissues, (b) active metabolites can be formed both in the liver and at extrahepatic sites, and they may not be sufficiently stable for transport from one site to another, and (c) regardless of the effect of pretreatment on pathways of extrahepatic metabolism, the accompanying effects on hepatic metabolism may determine the extrahepatic distribution and site of metabolism (in vivo) of a protoxin or its active metabolite(s). A review of studies on pulmonary toxicity produced by three agents--monocrotaline, bromobenzene, and 4-ipomeanol--illustrates several of these problems, and also shows the value of using inducers and inhibitors in the experimental analysis of extrahepatic toxicity produced by reactive metabolites.
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A sensitive and specific procedure for measuring plasma levels of pentamethylmelamine (PMM), a chemotherapeutic agent currently undergoing phase I trials, has been developed. PMM was isolated (recovery greater than 95%) from 3-ml plasma samples by cation exchange chromatography followed by solvent extraction, and was quantitated by selected ion monitoring with a gas chromatograph/mass spectrometer. Deuterium-labeled PMM was synthesized and used as an internal standard; standard curves were prepared by plotting m/e 196/199 ratios versus concentrations, and were linear in the range of 0.05-50.0 microM. The coefficient of variation for repeated measurements was less than 1% at all concentrations studied. To test the applicability of this method to clinical studies, plasma clearances of PMM were measured in two studies in each of three cancer patients receiving 80-mg/m2 doses of PMM as 1-hour iv infusions. Peak plasma concentrations, observed immediately after the end of the infusions, averaged 4.1 microM (SE = 0.6 microM). Plasma elimination was found to be biphasic; a short initial half-life (approximately 27 minutes) was followed by a longer elimination half-life of 133 minutes (SE = 35 minutes). Measurements in two patients indicated that less than 0.1% of the administered PMM was excreted unchanged in the urine in 24 hours, suggesting that hepatic metabolism of PMM may be a major contributor to plasma clearance of the drug in man.
Oral administration of carbon tetrachloride to rats or mice caused striking decreases in rat lung microsomal cytochrome P-450 and benzphetamine demethylase activity and in the enzyme-mediated covalent binding of 4-ipomeanol in preparations of rat and mouse lung microsomes, mouse lung slices and isolated whole-mouse lungs. Although it is not yet known whether cytochrome P-450 and benzphetamine demethylase activities are present in substantial amounts in more than one lung cell type in mice or rats, previous studies have indicated that cytochrome P-450 enzymes located in pulmonary bronchiolar Clara cells of these mediate the covalent binding of 4-ipomeanol to lung macromolecules. Histologic examinations of lungs of animals given doses of CCl4, orally or by inhalation, revealed striking morphologic changes in Clara cells, including severe dilation of endoplasmic reticulum and occasional cellular necrosis. Because of cytochrome P-450 enzymes are capable of mediating the formation of highly reactive and potentially toxic-free radicals from CCl4, the present results support the view that pulmonary Clara cells are susceptible to CCl4-induced injury due to their capacity to metabolically activate the chemical.
Using a new high-pressure anion-exchange chromatographic procedure, two radiolabeled conjugates were separated and assayed quantitatively from incubation mixtures containing lung or liver microsomes, NADPH, [3H]5-ipomeanol and glutathione. The same conjugates were obtained also from similar microsomal preparations containing unlabeled 4-ipomeanol, NADPH and [3H]glutathione. The conjugates were not produced in microsomal incubation mixtures containing only [3H]4-ipomeanol and glutathione, or [3H]4-ipomeanol and NADPH, or [3H]glutathione and unlabeled 4-ipomeanol, or in the presence of [3H]glutathione and NADPH alone. Unlike the parent 4-ipomeanol, the conjugates did not have detectable ultraviolet absorbance at 254 nm. Neither of the conjugates arose trough the reduction of 4-ipomeanol to 1,4-ipomeadiol, followed by further metabolism to a metabolite which reacted with glutathione. The total amounts of reactive 4-ipomeanol metabolites generated (estimated by by sum of conjugates plus covalently bound metabolites) were 2 to 3-fold greater in the presence than in the absence of glutathione. Soluble fraction preparations from homogenates of rat lungs or livers did not enhance the corresponding microsome-mediated production of either conjugate, suggesting that glutathione-transferase activities did not play a major role in glutathione conjugate formation with reactive 4-ipomeanol metabolites. The amounts of both conjugates were enhanced greatly in hepatic, but not pulmonary, microsome preparations from animals pretreated with phenobarbital or 3-methylcholanthrene. However, the ratios of the amounts of the two conjugates produced were similar in hepatic and pulmonary microsomal preparations from control rats, or from rats treated with either inducer. These results indicated that the reactive 4-ipomeanol metabolites formed during pulmonary compared to hepatic microsomal metabolism were similar. Moreover, the previously reported enhancement of the hepatic covalent binding and toxicity of 4-ipomeanol caused by pretreatment with 3-methylcholanthrene, but not by phenobarbital, was not likely due to a major change in the kinds or ratios of reactive 4-ipomeanol metabolites produced by hepatic microsomal enzymes after induction with 3-methylcholanthrene compared to phenobarbital.
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The preparation of a series of indole N-acyl and N-carbamic esters of (+/-)-alpha-5-[1-(indol-3-yl)ethyl]-2-methylamino-delta2-thiazolin-4-one (1) is reported. These derivatives were synthesized as potential water-soluble precursors of the antiviral thiazolinone 1, for evaluation by intranasal administration against influenza and other respiratory infections caused by viruses. Salts of the basic carbamic esters (16--19) possess the required water solubility, undergo rapid hydrolysis and decarboxylation at pH values greater than 6, and have high activity against influenza A2 and Coxsackie B1 viruses in vitro. In influenza A2 infected ferrets a representative ester (16) reduced the severity and duration of disease symptoms and reduced nasal wash virus titres but caused local irritancy.
The subcutaneous administration of nitrofurantoin to rats caused severe pulmonary damage, characterized by edema, congestion, and hemorrhage. The acute lethality of the drug was greater in rats fed vitamin E-deficient diets high in polyunsaturated fats as compared to rats fed the NIH open-formula diet. The survival times of vitamin E-deficient rats were increased if such animals were fed diets supplemented with vitamin E and/or diets containing saturated fat (lard) for 3 weeks before administration of nitrofurantoin. The toxicity of nitrofurantoin was enhanced in both the rats deficient in vitamin E and in those given vitamin E supplements and exposed to O2-enriched atmospheres. These results, in conjunction with previous metabolic studies in vitro showing redox cycling and O2 activation in rat lung microsomes in the presence of nitrofurantoin, illustrate certain similarities with the lung-toxic herbicide, paraquat, and raise the question of whether the 2 agents may be capable of damaging lungs by a common mechanism.
A new high-pressure liquid chromatographic method for the clinical assay of 5-fluorouracil and 5-fluoroudexyuridine has been developed. The sensitivity and specificity of the method equals that of gas chromatography/mass spectrometric methods. The practical value of the method has been demonstrated by its application in several preliminary clinical studies of 5-fluorouracil in which plasma levels of 10(-8)-10(-6)M were readily monitored.
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Total synthesis of a series of thiazolinone and thiazolidinone analogues of the antibacterial oxazolinone antibiotic indolmycin is described. The synthetic route involves nucleophilic displacement of mesyloxy and chloro groups from methyl 2-substituted-3-(indol-3-yl)propionates 3 and 4 and butyrate 19 with N-substituted thioureas. The formation of the rearranged chloro esters 29, 43, and 44 from beta(RS,RS)-methyl indolmycenate (27), alpha(RS,SR)-methyl 2-hydroxy-3-(2-methylindol-3-yl)butyrate (39), and alpha-methyl 2-hydroxy-3-(indol-3-yl)valerate (41) supports a reaction mechanism involving neighboring group participation by the indole C-3 carbon during nucleophilic displacement on the beta-carbon of a C-3 substituent. Structure-activity relationships are discussed. Although neither indolmycin nor its diastereoisomer isoindolmycin is antiviral, 2-monoalkylaminothiazolinone analogues have in vitro activity against both RNA viruses and bacteria. The most active compound is the sulfur isostere of indolmycin, and only the levorotatory enantiomer 46, with the same absolute stereochemistry as natural indolmycin, has antimicrobial activity.
Rat lung and liver microsomes mediated the biotransformation of the pulmonary toxin, 4-ipomeanol, to an alkylating metabolite. The enzyme-mediated microsomal alkylation required NADPH and oxygen and was strongly inhibited by carbon monoxide, which indicated the participation of a cytochrome P-450-dependent monooxygenase. Other studies with inhibitors including pyrazole, piperonyl butoxide, SKF-525A, and cobaltous chloride, and with the inducers phenobarbital and 3-methylcholanthrene, also were consistent with this view. The Km for the pulmonary microsomal alkylation pathway was more than 10-fold lower than for the hepatic microsomal pathway. There was no significant enzyme-mediated covalent binding of analogs of 4-ipomeanol lacking the furan moiety, suggesting that metabolic activation of the parent compound involves oxidation of the furan ring. Reduced glutathione prevented the microsomal alkylation by 4-ipomeanol, indicating the electrophilic nature of the alkylating metabolite.
The pulmonary toxin, 4-ipomeanol, selectively alkylates the lungs of rats. Time-course and dose-response studies demonstrate a close correlation between the pulmonary alkylation and the lung toxicity of the compound. Without prior metabolism, 4-ipomeanol is not sufficiently reactive to alkylate tissue macromolecules. Inhibitors of the metabolism of 4-ipomeanol decrease both the pulmonary alkylation and toxicity of the compound, which suggests that the toxicity is due to an alkylating metabolite. Studies with inducers of the hepatic metabolism of 4-ipomeanol are consistent with the view that the toxic metabolite of the compound is actually formed in situ in the target tissue. Pretreatment of animals with diethylmaleate strikingly increases both the pulmonary alkylation and the lung toxicity of 4-ipomeanol. Studies of the tissue alkylating properties and toxicities of 4-ipomeanl analogs demonstrate the requirement for the furan moiety. The toxic metabolites of 4-ipomeanol appears to be a highly electrophilic reactant capable of binding irreversibly with nucleophilic macromolecular constituents of target tissue.