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PubMed2001

Bioaccumulation of polychlorinated biphenyls (PCBs) and dichlorodiphenylethane (DDE) methyl sulfones in tissues of seal and dolphin morbillivirus epizootic victims.

Polychlorinated biphenyl (PCB) and dichlorodiphenylethane (DDE) methyl sulfone (MSF) metabolites possess high affinities for binding two homologous 16,000 Da homodimeric receptor proteins in the lung (Clara cell secretory protein, CCSP) and the uterus (uteroglobin, UG), leading to selective bioaccumulation of MSFs in these tissues. As marine mammals are highly exposed to organochlorines, concentrations of PCBs, PCB MSFs, DDT, and DDE MSF were analyzed in blubber, lung, and uterus samples from harbor seal (Phoca vitulina) and striped dolphin (Stenella coeruleoalba) morbillivirus epizootic victims to investigate uterine and lung MSF accumulation. Mean uterus concentrations of PCB MSFs and DDE MSF in harbor seals were 0.61 and 0.04 microg/g lipid weight and in striped dolphins 0.05 and 0.01 microg/g lipid weight. Mean lung concentrations of PCB MSFs and DDE MSF in harbor seals were 0.96 and 0.02 microg/g lipid weight and in striped dolphins 0.16 and 0.01 microg/g lipid weight. To ascertain whether uterine and lung bioaccumulation of MSFs is possible due to the presence of CCSP and UG in seals, CCSP and UG proteins in uterine flushings and in uterine and lung and epithelial tissue from Baltic gray and ringed seals were characterized using gel electrophoresis and Western blotting techniques. UG- and CCSP-like proteins with molecular weights of 16,000 Da were resolved in all samples. This is the first demonstration of this protein in any marine mammalian species. The toxicological implications of MSF binding with UG and CCSP in marine mammals are discussed.

Adipose Tissue↗
PubMed1999

Effects of bis(4-chlorophenyl) sulfone on rats following 28-day dietary exposure.

The short-term oral toxicity of a recently identified environmental pollutant, bis(4-chlorophenyl) sulfone (BCPS), was studied. Groups of male Sprague-Dawley rats (n = 6) were administered BCPS via the diet at 0 (control), 10, 100, or 1000 ppm for 4 wk. Additional control and 1000 ppm groups were also treated for 1, 2, and 3 wk. At termination, high-dose animals showed depressed growth rate and food consumption, and 1 high dose animal in each of the wk-1, -3, and -4 groups had marked hematuria. Increased liver to body weight ratio was present at 100 ppm and increased kidney to body weight ratio at 1000 ppm. Marked increases in hepatic benzoylresorufin O-dealkylase (BROD) and pentoxyresorufin O-dealkylase (PROD) activities were detected starting at 10 ppm. There was a significant decrease in methoxyresorufin O-dealkylase (MROD) activity at 1000 ppm. Hepatic UDP-glucuronosyltransferase (UDPGT) and glutathione S-transferase (GST) activities also increased starting at 100 ppm. A marked increase in urinary excretion of ascorbic acid was apparent starting at 10 ppm, while there were no changes in urinary N-acetylglucosaminidase (NAG) activity and protein levels. A threefold increase in serum cholesterol and a 30% increase in platelet counts were observed in the 1000 ppm group. Levels of thiobarbituric acid-reactive substances (TBARS) were increased by threefold in the liver of the high-dose animals but were not significantly altered in the serum. Tissue BCPS concentrations were dose dependent and followed the order: adipose tissue >>> liver > kidneys > brain, spleen, lungs. In the time-course study involving the control and high-dose groups, most of the treatment effects were clearly present in wk 1, and the severity of the effects remained at more or less the same levels thereafter. The exceptions were hepatic BROD and PROD activities, which showed a trend toward further increases with time of treatment. Liver and adipose tissue concentrations of BCPS remained unchanged from wk 1 to wk 4, while kidney concentrations increased with time. The results indicated that BCPS produced hepatic effects at the lowest dose level tested (10 ppm in the diet or 0.8 mg/kg/d).

Administration, Oral↗
PubMed1973

Immunological tolerance to a hapten. I. Induction and maintenance of tolerance to trinitrophenyl with trinitrobenzene sulfonic acid.

Treatment of mice with a nonimmunogenic preparation of free reactive hapten, trinitrobenzene sulfonic acid (TNBS), leads to the induction of a state of tolerance to the hapten, 2,4,6-trinitrophenyl (TNP). This is determined by the lack of response to the haptenic moiety in an immunogenic hapten-carrier conjugate (TNP-SRBC) as assayed both by serum antibody titrations and the hemolytic plaque assay. The tolerance produced is specific for the hapten, since the anticarrier responses are essentially unaltered compared with the control values. The unresponsiveness induced by TNBS treatment is a dose-dependent phenomenon, becoming less complete at lower doses of TNBS. The tolerance is of a definite length, both in its induction phase and in the duration of the established unresponsive state. Tolerance can be maintained and extended, and may also be reentered once escape has been initiated.

Animals↗
PubMed1973

Inhibition of amino acid transport in rabbit intestine by p-chloromercuriphenyl sulfonic acid.

Influx of phenylalanine across the brush border of rabbit intestine is markedly reduced by treatment with 5 mM p-chloromercuriphenyl sulfonate (PCMBS). The effect is rapidly and completely reversed by dithiothreitol. Phenylalanine influx into PCMBS-treated tissue can be competitively inhibited by other neutral amino acids and follows saturation kinetics. PCMBS causes an increase in the apparent Michaelis constant from the value observed in control tissue but does not alter the maximal influx significantly. Treatment of the tissue with PCMBS leads to a significant reduction in the Na-sensitivity of the transport, and a number of results indicate that the major effect of the reagent is to cause a marked reduction in the affinity of the transport system for Na. The transport system can be partially protected against reaction with PCMBS by phenylalanine and tryptophan but not by methionine or norleucine. The results suggest that PCMBS reacts with a sulfhydryl group in the region of the transport site and may alter conformational changes associated with the binding of substrates.

Amino Acids↗
PubMed1997

Pilot ascending dose tolerance study of parenterally administered 4-(2 hydroxyethyl)-1-piperazine ethane sulfonic acid (TVZ-7) in dogs.

We report a pilot toxicity study in healthy beagle dogs which revealed no significant adverse events for TVZ-7 given at i.v. doses up to 520 mg/kg/day. All treated dogs displayed calm behavior and maintained normal clinical laboratory values throughout the study. Increased bone marrow hypercellularity and extramedullary hematopoiesis was also noted in these dogs. Three other dogs with advanced spontaneously occurring tumors have also been dosed. No serious adverse events were reported in any of the dogs. This pilot study suggests that 4-(2 Hydroxyethyl)-1-piperazine ethane sulfonic acid may be used safely in planned human clinical trials.

Alkanesulfonic Acids↗
PubMed1995

X-ray crystal structure of a dimethylene sulfone-bridged ribonucleotide dimer in a single-stranded state.

A crystal structure has been solved for an analog of the r(ApU) ribodinucleotide, r(Aso2U), where a bridging non-ionic dimethylene sulfone linker replaces the phosphodiester linking group found in natural RNA. Crystals of the single-stranded state of r(Aso2U) were obtained from water at 50 degrees C. In these crystals, one hydrogen bond is formed between bases from different strands and base stacking occurs in intermolecular 'homo-A' and 'homo-U' stacks. Similar to typical oligoribonucleotides, the ribose rings adopt N-type conformations and dihedral angles chi are in the anti range. The all-trans rotamer of the CH2-SO2-CH2-CH2 bridge was found, which leads to a large adenine-uracil distance. Qualitative analysis of a NOESY spectrum of the Aso2U part in r(Uso2Cso2Aso2U) dissolved in a dimethylsulfoxide-D2O mixture indicates that the conformation observed in the crystal is also populated in solution. Comparison with the structure of r(Gso2C), which has been crystallized in the Watson-Crick paired state, shows that a rotation around zeta by +112 degrees leads from the observed, single-stranded state to a conformation that is compatible with formation of a duplex. A concerted trans/gauche flip of alpha and gamma then yields the standard conformer of A-type RNA helices. From the observed structure of r(Gso2C) and other oligonucleotides it is anticipated that this flip will also revert the ribose pucker from C2'-exo to C3'-endo.

Adenine↗
PubMed1976

Reconstruction of intact gamma-globulin from S-sulfonated gamma-globulin in vivo.

The conversion of the S-surfonate group in a peptide to a disulfide bond has been observed in vitro. This paper reports that the conversion of this group in human S-sulfonated gamma-globulin (S-GG) appeared to occur in vivo judging from the change in molecular weight of S-GG observed in the presence of sodium dodecyl sulfate (SDS) and the restoration of hemolytic activity.

Animals↗
PubMed2001

Toxicology and carcinogenesis studies of p,p'-dichlorodiphenyl sulfone in rats and mice.

p,p'-Dichlorodiphenyl sulfone (DDS) is used as a starting material in the production of polysulfones and polyethersufones, a family of thermoplastics. DDS was studied because of its high production volume and use. In toxicology studies, 10 Fischer 344 rats and 10 B6C3F1 mice/sex/group were fed diets containing 0, 30, 100, 300, 1,000 or 3,000 ppm DDS for 14 weeks. All animals survived until the end of the studies. Mean body weights of groups exposed to 300 ppm or greater were significantly decreased. Liver and kidney in rats and liver in mice were the major target organs of DDS toxicity. Dose-related increases in liver weights and incidences of centrilobular hepatocyte hypertrophy were observed in DDS-exposed groups. Nephropathy was seen in male and female rats only at and above 300 ppm. Neurotoxicity evaluations were negative in DDS-treated animals. Clinical chemistry and hematology parameters were minimally affected. In the 2-year toxicity and carcinogenicity studies, 50 rats and 50 mice/sex/group were fed diets containing 0, 10 (male rats), 30, 100, or 300 ppm DDS for 104 to 105 weeks. Survival of exposed groups was not affected. There were no clinical signs of toxicity related to DDS exposure. Final mean body weights were 2-17% lower in DDS-treated groups. Liver was the only target organ of DDS-induced toxicity. The incidence of centrilobular hepatocyte hypertrophy in mice and rats, and the incidence of bile duct hyperplasia and centrilobular degeneration in female rats was significantly greater than in controls. A no-observed-adverse-effect level (NOAEL) of 30 ppm DDS in the diet (1.5 mg/kg body weight) was established for rats. DDS was not carcinogenic in these studies.

Animals↗
PubMedDate not supplied

Synthesis of aromatic polyimides with sulfone diamine moieties for a novel membrane oxygenator.

The authors have synthesized soluble aromatic polyimides derived from 2,2'-bis(3,4-dicarboxyphenyl) hexafluoropropane dianhydride (6FDA) and 3,3'- or 4,4'-diamino-diphenylsulfone (m-DDS or p-DDS) to develop a novel membrane oxygenator. Asymmetric gas exchange membranes for the oxygenator were prepared by a dry/wet phase inversion process. The resulting membrane structure consisted of an ultrathin, selective, and defect free skin layer supported by a porous substructure. The membranes exhibited extremely high gas flux and selectivity. CO2 flux through the polyimide membranes used in this study increased with a decrease in CO2 pressure and was in accordance with the dual mode transport described by a combination of the Henry and Langmuir modes. This indicates that CO2 is selectively removed from the membranes at low CO2 pressure as compared with presently available materials for membrane oxygenators, such as polydimethylsiloxane and polypropylene. The number of platelets adherent to the surface of the polyimide were significantly smaller than those on polydimethylsiloxane and polypropylene, and the deformation and aggregation of platelets on polyimide were not observed. These findings suggest that aromatic polyimides with sulfone diamine moieties are promising membrane materials for an oxygenator.

Biocompatible Materials↗
PubMed1975

Reactions of proteins with ethyl vinyl sulfone.

Ethly vinyl sulfone (EVS) alkylates xi-amino groups of lysine side chains and imidazole groups of histidine residues in proteins. Amino acid analysis of hydrolyzates of EVS-treated polylysine shows that lysine forms two derivatives, presumably xi-N-(ethylsulfonylethyl)lysine and xi, xi, N,N-bis(ethylsulfonylethyl)lysine that are eluted as well-resolved peaks on the (long basic) physiological column of our amino acid analyzer at about 118 and 60 min, respectively. Peaks with identical elution times were also observed after EVS-treatment of BSA and wool. The postulated histidine derivative, presumably N3-im-(ethylsulfonylethyl)histidine is also eluted as a well-resolved peak on the same column at about 90 min. A peak with an identical elution time was observed in a hydrolyzate of EVS-treated polyhistidine. The described alkylation has potential utility for modifying proteins.

Alkylation↗
PubMed2006

In vivo biocompatibility of sulfonated PEO-grafted polyurethanes for polymer heart valve and vascular graft.

Sulfonated poly(ethylene oxide) (PEO)-grafted polyurethane (PU) (PU-PEO-SO(3)) prepared by bulk modification was used to coat both PU heart valves and vascular grafts, and their in vivo biocompatibility was evaluated using a canine shunt method. The two devices were implanted for up to 39 days and retrieved at specific time points for the analysis of blood compatibility, biostability, and calcium deposition. When the surface of the retrieved specimens was examined using scanning electron microscopy, platelet adhesion and thrombus formation appeared to be significantly lesser formed on the PU-PEO-SO(3)-coated implants, compared with the untreated PUs. While molecular weights of untreated PUs were found by gel permeation chromatography to be decreased after 39 days from implantation, the same remained barely changed with the PU-PEO-SO(3)-coated ones. The inductively coupled plasma study indicated that the amount of deposited calcium was significantly reduced in the surface-modified PU implants. The efficacy of PU-PEO-SO(3)-coated implants in terms of blood compatibility, biostability, and calcification resistance may render them as a promising biomedical material in the application for blood/tissue-contacting tissues and organs.

Animals↗
PubMed1989

Effect of photodynamic therapy on anti-tumor immune defenses: comparison of the photosensitizers hematoporphyrin derivative and chloro-aluminum sulfonated phthalocyanine.

The effects of the two photosensitizers chloroaluminum sulfonated phthalocyanine (ClAlSPc) and hematoporphyrin derivative (HpD) on the functional activities of macrophages and natural killer (NK) cells, two immunocyte populations implicated in the control of tumor development and spread, have been investigated. Murine peritoneal macrophages treated in vivo with ClAlSPc or HpD at 10 mg/kg body weight showed no impairment of Fc-mediated phagocytic capacity and only minor disturbances of in vitro tumoricidal/tumoristatic function. The NK cell activity of splenocytes obtained from photosensitizer-treated mice, assayed 24 or 48 h after i.v. injection of ClAlSPc or HpD at 10 mg/kg was unaffected compared to controls. However significant inhibition of NK activity was observed when splenocytes obtained from mice with or without subcutaneous Colo 26 tumors, treated with ClAlSPc plus laser therapy (675 nm) were used as effector cells. The results show that impairment of some anti-tumor activity can be observed in phthalocyanine treated or phthalocyanine + laser-treated animals but this relatively minor impairment may augur well for the use of systemic phthalocyanine administration in photodynamic therapy.

Animals↗
PubMed1994

A comparison of direct and liposomal antibody conjugates of sulfonated aluminum phthalocyanines for selective photoimmunotherapy of human bladder carcinoma.

There is a need to improve the selectivity of photodynamic therapy and for better targeting of tumor cells within specific tumor compartments. Selective in vitro phototoxicity of a human bladder carcinoma cell line 647V has been achieved by targeting sulfonated aluminum phthalocyanines (AlSPc) with monoclonal antibodies. Aluminum tetra-3 sulfonyl chloride phthalocyanine (PC) or rhodamine sulfonyl chloride were directly coupled to antibodies by a sulfonamide linkage and AlSPc or carboxyfluorescein were encapsulated in liposomes of the small unilamellar vesicle type (SUV) bearing antibody. Antibody E7 (IgM subclass), which recognized an antigenic determinant expressed on 647V but was absent on T24 a control human bladder carcinoma cell line, and a control IgM antibody were used. The effects of the two types of conjugate were compared. Immunofluorescence studies on living cells demonstrated specific cell surface localization of conjugates at 4 degrees C and internalization at 37 degrees C. Phototoxicity was measured by 3-(4,5-dimethylthiazol-2-5-diphenyltetrazolium) bromide assay after exposing AlSPc-sensitized cells to red light. Significant AlSPc dose-dependent phototoxicity of the order 4 degrees C < 4 degrees C plus 37 degrees C < 37 degrees C was observed with E7-SUV and E7-PC in the range 1-8 microM AlSPc. At equimolar AlSPc doses absolute toxicity was similar for the two conjugate types, but at equimolar antibody doses, the liposomal conjugate was more effective by up to 13-fold. Addition of urine during illumination decreased toxicity, which was attributed to the presence of protective elements. The results suggest that photosensitizers such as AlSPc could be used for antibody-directed therapy and in particular for selectively damaging tumor cells of the epithelial cell compartment in bladder carcinoma by intrabladder administration. The therapeutic ratio, which takes into account both specific and nonspecific toxicity, was greater for the liposome conjugate than for the direct conjugate indicating their greater suitability for in vivo instillation.

Aluminum↗
PubMed2006

Formation of N-alkylprotoporphyrin IX from metabolism of diallyl sulfone in lung and liver.

Diallyl sulfone (DASO2) is a garlic derivative formed during cooking or after ingestion. Bioactivation of DASO2 in murine lung and liver results in formation of an epoxide that inactivates CYP2E1 and significantly decreases cytochrome P450 and heme levels. In this study, we tested the hypothesis that DASO2 metabolism leads to production of the heme adduct, N-alkylprotoporphyrin IX (N-alkylPP). Formation of N-alkylPP in vivo and in vitro was determined by spectrophotometric and fluorometric methods, respectively. In in vivo studies, N-alkylPP was generated in the livers of male and female mice treated with DASO2, but was not detectable in the lungs of DASO2-treated mice. In in vitro studies, rates of formation of N-alkylPP in liver and lung microsomes incubated with DASO2 and NADPH were dependent on time and protein concentrations, but were negligible in control incubations performed in the absence of NADPH or DASO2 or with boiled microsomes. The rates of N-alkylPP formation generated in murine liver were higher than those in either murine lung or human liver. Kinetic analysis revealed that murine liver microsomes metabolized DASO2 to N-alkylPP with higher affinity and catalytic efficiency than did murine lung or human liver microsomes. Recombinant rat CYP2E1 also metabolized DASO2 to N-alkylPP; however, rates of formation of the heme adduct was minimal in incubations of recombinant human CYP2E1 with DASO2. These findings demonstrated that the N-alkylPP adduct was produced via metabolism of DASO2 in murine liver and lung microsomes, in human liver microsomes, in recombinant CYP2E1, and in vivo in murine liver.

Alkylation↗
PubMed2003

Metabolism of (R)-(+)-menthofuran in Fischer-344 rats: identification of sulfonic acid metabolites.

(R)-(+)-Menthofuran is a metabolite of (R)-(+)-pulegone, the chief constituent of pennyroyal oil. Menthofuran has been shown to account for a significant percentage of pulegone toxicity through further metabolism to a reactive intermediate, an enonal (2-Z-(2'-keto-4'-methylcyclohexylidene)propanal). Hydration of the enonal followed by a 1,4-dehydration and rearrangement gives rise to diastereomeric (-)-mintlactone and (+)-isomintlactone (mintlactones). We have conducted disposition studies on pulegone as part of the National Toxicology Program initiative in herbal medicines and dietary supplements, and have reported previously unknown urinary metabolites of pulegone. Comparative metabolism studies of 14C-labeled menthofuran in Fischer-344 (F344) rats were carried out to determine urinary metabolites of pulegone that are derived from the menthofuran pathway. Three sulfonic acid metabolites, namely, hexahydro-3,6-dimethyl-1-(2-sulfoethyl)-2H-indol-2-one, hexahydro-3,6-dimethyl-7a-sulfo-2(3H)-benzofuranone, and 2-sulfomenthofuran, were identified in urine of treated rats. Formation of these metabolites may be derived from reactions of the enonal with taurine or glutathione (GSH) (or sulfite ion). Other identified urinary metabolites of menthofuran could be attributed to further metabolism of mintlactones. Further hydroxylation of mintlactones could give 7a-hydroxymintlactone and 6,7a-dihydroxymintlactone. Glucuronidation or reduction of 7a-hydroxymintlactone could give rise to the major metabolites 7a-hydroxymintlactone glucuronide and 2-[2'-keto-4'-methylcyclohexyl]propionic acids. Glucuronidation or repeated hydroxylation/dehydration of 2-[2'-keto-4'-methylcyclohexyl]propionic acids could result in formation of hexahydro-3,6-dimethyl-7a-hydroxy-2(3H)-benzofuranone glucuronide and 2-(2'-hydroxy-4'-methylphenyl)propionic acid. 2-(Glutathion-S-yl)menthofuran, a GSH conjugate of the enonal that has been partially characterized in bile of rats dosed with pulegone, is at most a minor biliary metabolite of menthofuran in rats.

Animals↗
PubMed2002

Characterization of the diarylether sulfonylester (-)-(R)-3-(2-hydroxymethylindanyl-4-oxy)phenyl-4,4,4-trifluoro-1-sulfonate (BAY 38-7271) as a potent cannabinoid receptor agonist with neuroprotective properties.

(-)-(R)-3-(2-Hydroxymethylindanyl-4-oxy)phenyl-4,4,4-trifluoro-1-sulfonate (BAY 38-7271) is a new high-affinity cannabinoid receptor subtype 1 (CB1 receptor) ligand (K(i) = 0.46-1.85 nM; rat brain, human cortex, or recombinant human CB1 receptor), structurally unrelated to any cannabinoid receptor ligand known so far. BAY 38-7271 was characterized as a CB1 receptor agonist in 5-[gamma(35)S]-thiophosphate triethylammonium salt binding assays using rat or human CB1 receptors. In the rat hypothermia assay, BAY 38-7271 induced a dose-dependent reduction in body temperature (minimal effective dose = 6 microg/kg, i.v.); whereas in rats trained to discriminate the CB1/CB2 receptor agonist (-)-cis-3-[2-hydroxy-4(1,1-dimethyl-heptyl)phenyl]-trans-4-(3-hydroxypropyl) cyclohexanol (CP 55,940; 0.03 mg/kg, i.p.) from vehicle, BAY 38-7271 induced complete generalization (3 microg/kg, i.v.). In both in vivo models, a specific CB1 receptor-mediated mechanism was confirmed by demonstrating that the effects of CP 55,940 and BAY 38-7271 were blocked by pretreatment with the selective CB1 receptor antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamidehydrochloride. In the rat traumatic brain injury model, BAY 38-7271 demonstrated highly potent and efficient neuroprotective properties when administered as a 4-h infusion immediately after induction of subdural hematoma (70% infarct volume reduction at 100 ng/kg/h). Even when applied with a 3-h delay, a significant neuroprotective efficacy could be observed (59% infarct volume reduction at 300 ng/kg/h). The neuroprotective potential of BAY 38-7271 was confirmed in a rat model of focal cerebral ischemia induced by permanent occlusion of the middle cerebral artery. It is concluded that the CB1/CB2 receptor agonist BAY 38-7271 shows pronounced neuroprotective properties that do not result from drug-induced hypothermia and that occur in a dose range devoid of typical cannabinoid-like side effects.

Animals↗
PubMed1972

Antimycobacterial activity of some quinolyl aryl sulfides, sulfones, and ethers, in vitro.

A series of 61 compounds of six different categories (nitrosulfides, nitrosulfones, aminosulfides, aminosulfones, nitroethers, and aminoethers), all heterocyclic analogues of diaminodiphenyl sulfone (DADS), were synthesized by replacing one of the benzene rings of DADS by a 5-nitro-quinoline ring and the other benzene ring by various heterocyclic nuclei. Among these compounds, 51 were found to inhibit the growth of Mycobacterium tuberculosis at a concentration of 40 mug or less per ml; 8 compounds were effective at a concentration of 1 mug/ml and 9 were effective at a concentration of 0.1 mug/ml. 5-Amino-8-quinolyl-2,4-dichlorophenyl sulfide was found to be 20 times more effective than isonicotinic acid hydrazide and 80 times more effective than streptomycin.

Ethers↗
PubMed1987

In vitro activity of sulfonamides and sulfones against Leishmania major promastigotes.

We examined the susceptibility of promastigotes of Leishmania major to sulfonamides and sulfones in vitro. In a completely defined medium only sulfamoxole, sulfaquinoxaline, and dapsone were inhibitory; the concentrations required for 50% inhibition of the rate of growth were 150, 600, and 600 microM, respectively. Eleven other sulfa drugs were ineffective at concentrations up to 2 mM. The growth inhibition was similar to that observed in procaryotes: the cells continued logarithmic growth for several cell doublings before inhibition was observed. Surprisingly, the addition of p-aminobenzoate or folate did not reverse the effects of the active sulfa drugs, the effects of sulfamoxole and methotrexate were additive rather than synergistic, and the addition of thymidine reversed methotrexate but not sulfa-drug inhibition. These results suggest that the mode of action of sulfa drugs on L. major is not by the classical route of inhibition of de novo folate synthesis. Promastigotes could be propagated for more than 40 passages in a completely defined medium in which the only added pterin was biopterin. The folate concentration in this medium was less than 10(-10) to 10(-11) M, as determined by a Leishmania bioassay. Although these data suggest that L. major may be capable of de novo synthesis of folate, the nonclassical mode of action of sulfa drugs, as well as other studies, favors the view that L. major is auxotrophic for folate.

Animals↗