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The treatment of hypertension in pregnancy.

The drug treatment of hypertension occurring during pregnancy is described. Diagnostic problems and management are outlined, and the available literature regarding the use of standard hypotensive agents in pregnancy is reviewed by drug class. Based on currently published literature and opinion, the following drugs are recommended when needed during pregnancy (with proper monitoring) : methyldopa, hydralazine, and furosemide. Caution is recommended when the following drugs are used during pregnancy: propranolol, and thiazide diuretics. The following drugs are not recommended for use during pregnancy based on currently available information: reserpine, clonidine, chlorthalidone, prazosin, minoxidil, spironolactone, ethacrynic acid, metoprolol, nadolol, and guanethidine.

Adrenergic beta-Antagonists↗

Pharmacology of Bay g 2821, a long-acting, high-ceiling diuretic.

Bay g 2821 is a diuretic, from a new class of chemical substances, with both the efficacy of diuretics with a high-ceiling activity, such as furosemide, bumetanide and ethacrynic acid, and the prolonged duration of action of thiazides. Pharmacological investigations showed that Bay g 2821 was more potent than furosemide in dogs but less potent in rats. Bay g 2821 did not differ from furosemide in excretion of electrolytes. Further studies showed that Bay g 2821 had an antihypertensive effect in dogs, spontaneously hpertensive rats, and in rats with artificially-induced renal hypertension. Other pharmacological studies did not reveal any other significant effects.

Animals↗

Effects of cigarette smoke with different tar contents on hepatic and pulmonary xenobiotic metabolizing enzymes in rats.

The effects of smoke from cigarettes with two different tar contents (32 mg/cigarette, high tar, and 15 mg/cigarette, low tar) on hepatic and pulmonary monooxygenase (MO) activities (aniline 4-hydroxylase [AH]; aminopyrine N-demethylase [AMND]; 7-ethoxyresorufin O-deethylase [EROD]; p-nitroanisole O-demethylase [p-NAOD]), lipid peroxidation (LP) and reduced glutathione (GSH) levels and glutathione S-transferase (GST) activities toward several substrates (1-chloro-2,4-dinitrobenzene [CDNBI; 1,2-dichloro-4-nitrobenzene [DCNB]; ethacrynic acid [EAA]; 1,2-epoxy-3-(p-nitrophenoxy)-propane [ENPP]) were determined in adult male rats. Adult male rats were exposed to smoke of high- or low-tar cigarettes five times a day, with 1-hour intervals, for 3 days in a chamber where smoke and fresh air lead alternatively and were killed 16 hours after the last treatment. Smoke of both high- and low-tar cigarettes (SHTCC and SLTCC) significantly increased hepatic and pulmonary EROD and p-NAOD activities compared to controls. However, the increase noted by SHTCC on pulmonary EROD activity was higher than that of SLTCC. Hepatic AMND and pulmonary AH activities were significantly increased only by SHTCC. LP level was significantly decreased and increased by SHTCC in liver and lung, respectively, whereas it remained unaltered by SLTCC. Only SHTCC significantly increased GSH level in liver. In the lungs, both SHTCC and SLTCC significantly increased GSH level to the same extent. Hepatic GST activity toward EAA was significantly increased by SHTCC but was significantly decreased by SLTCC. ENPP GST activity was significantly decreased by SHTCC and SLTCC in the livers. In the lungs, all the GST activities examined were significantly depressed by SHTCC whereas only GST activity toward DCNB was reduced significantly by SLTCC. These results reveal that the hepatic and pulmonary MOs and GSTs are differentially influenced by SHTCC and SLTCC in rats.

Administration, Inhalation↗

Rapid and reversible changes in dendrite morphology and synaptic efficacy following NMDA receptor activation: implication for a cellular defense against excitotoxicity.

Postsynaptic neuronal dendrites undergo functional and morphological changes in response to pathologically excessive synaptic activation. Although rapid formation of segmental focal swelling (varicosity) is the most prominent hallmark in such excitotoxic injury, little is known about the pathophysiological function of these structural alterations. We used cultured rat hippocampal slices to evaluate the relationship between the formation of varicosities and subsequent neuronal death. Substantial numbers of segmental dendritic varicosities were observed all over the hippocampus within 5 minutes of exposure to 30 microM NMDA, although neuronal death was detected only in the CA1 region 24 hours after NMDA exposure. Sublethal NMDA concentrations (1-10 microM) induced reversible focal swelling in all hippocampal subregions. NMDA-induced neuronal death was prevented either by NMDA receptor antagonists or by the use of Ca(2+)-free medium, whereas varicosity formation was virtually independent of Ca(2+) influx. Rather, the Ca(2+)-free conditions per se produced dendritic focal swelling. Also, NMDA-induced varicosity formation was dependent on extracellular Na+ concentration. Thus, we believe that varicosity formation is not causally related to neuronal injury and that the two phenomena are separable and involve distinct mechanisms. Interestingly, dendrite swelling was accompanied by AMPA receptor internalization and a rapid, long-lasting depression in synaptic transmission. Moreover, low Na+ conditions or treatment with ethacrynic acid or proteinase inhibitors, which effectively prevent varicosity formation, aggravated NMDA-induced excitotoxicity, and eliminated the regional specificity of the toxicity. Therefore, the pathological changes in dendrite morphology and function may be associated with an early, self-protective response against excitotoxicity.

Animals↗

Factors affecting glomerular function in the pacific hagfish Eptatretus stouti (Lockington).

Single glomerulus filtration rate in Eptatretus stouti averaged 20.3+/-2.13 (S.E.M.) nl min(-1). Single glomerulus glomerular filtration rate (GFR) could be correlated with arterial pressure when arterial pressure exceeded about 4 cm H2O. Glomerular filtration was affected by postglomerular resistance brought about by alteration of the volume of urinary spaces. Filtration undoubtedly plays a role in glomerulus function. However, average colloid osmotic pressure (COP) of the plasma is almost double the average hydrostatic pressure in the segmental arteries serving the glomeruli. The COP of glomerular fluid is essentially nil, therefore it is difficult to see how pressure filtration alone can account for primary urine formation. When single glomeruli were perfused with colloid-containing Ringer at pressures within the normal range of blood pressures, GFR was within the normal range. GFR was related inversely to the colloid osmotic pressure of the perfusion Ringer. Colloid entered the urine during perfusion. However, in only a few instances did this result in conditions favourable to pressure filtration. To assess the role of active processes in glomerular filtration, chemical inhibitors were added to the perfusion Ringer. Amiloride, acetazolamide, cyanide, 2-deoxy-D-glucose, iodoacetate and ethacrynic acid were without marked effect on glomerular filtration. Ouabain and dinitrophenol markedly reduced GFR; inhibition was probably not due to indirect effects upon the renal vasculature.

Animals↗

[Properties of ATP-dependent H+-transport in rat brain synaptosomes].

Properties of the ATP-dependent H+-transport system in rat brain synaptosomes were examined using the acridine orange fluorescence quenching method. ATP-dependent H+-accumulation assessed by the quenching of acridine orange fluorescence was observed with the synaptosomes treated with hypotonic solution (hypotonic shock-synaptosomes), but not with the intact synaptosomes. With hypotonic shock-synaptosomes, H+-transport was activated in the presence of Cl- or Br-. However, this transport activity was markedly reduced in the presence of Mes-, NO3-, I- or SCN-. On the other hand, H+-transport activity was less effective with cations other than K+ in the following decreasing order of potency: K+ greater than Cs+ greater than Na+ greater than Li+. The H+-transport activity was inhibited by 0.3 mM ethacrynic acid, 10 microM 4-acetamide-4'-isothiocyanostilbene-2,2'-disulfonic acid or 1 mM 4-aminopyridine to 39.2%, 36.3%, or 33.1% of the control, respectively, but was not inhibited by 1 mM ouabain, 500 microM vanadate, 10 microM picrotoxin and 100 microM gamma-aminobutyric acid. These results suggest that the ATP binding site of the synaptosomal ATP-dependent H+-transport system exists on the internal surface of synaptosomal plasma membranes and that the H+-transport system is stimulated by the presence of Cl- or Br- and by K+ movement through the K+ channel.

Adenosine Triphosphate↗

[Effect of ethanol on synaptosomal membrane potential in the rat brain].

The membrane potential of rat brain synaptosomes was depolarized by ethanol at concentrations of over 0.8-1.6%. This ethanol-induced depolarization was augmented by 4-aminopyridine (4-AP) or the gluconate- -medium, but not affected by tetrodotoxin, choline-Cl, NH4Cl, picrotoxin, ethacrynic acid, furosemide or SCN- -medium. The ethanol-induced depolarization was augmented by 4-AP in Cl- - or gluconate- -medium, but not in SCN- -medium. These findings suggest that ethanol depolarizes the synaptosomal membrane potential through potassium and anion-related mechanisms, probably through potassium channels.

4-Aminopyridine↗

Divalent cation transport in kidney slices. I. Properties of calcium transport in slices of rat kidney cortex and the effects of diuretics.

Correlative studies on transports of Ca2+ and Na+ and the properties of Ca2+ transport were carried out in rat kidney cortex slices. Ouabain had no effect on the Ca2+ transport but did inhibit the Na+ transport extensively. With addition of 2,4-dinitrophenol to the incubation medium, or under the anaerobic conditions, the effluxes of Ca2+ and Na+ were inhibited while the Ca2+ influx was enhanced significantly. Sulfhydryl inhibitors such as ethacrynic acid, mersalyl and p-chloromercuribenzoic acid suppressed Ca2+ efflux and stimulated Ca2+ influx. When the slices of kidney cortex were treated with these inhibitors, there was a reduction in the content of cellular ATP. The present results suggest that Ca2+ transport may be partly independent of Na+ transport, and that Ca2+ efflux may require energy-yielding processes.

Adenosine Triphosphate↗

Divalent cation transport in kidney slices II. Magnesium transport in kidney cortex slices and effects of diuretics.

We examined the properties of Mg2+ transport in rat kidney cortex slices and the effects of diuretics were also studied. Incubation with 1 mM 2,4-dinitrophenol, or under anaerobic conditions, sharply inhibited Mg2+ influx, while markedly stimulating Mg2+ efflux. Under conditions of hypothermia, partial inhibition of Mg2+ influx and significant enhancement of Mg2+ efflux were observed. Mg2+ influx was not affected by ouabain, by altering CaCl2 concentration in the medium, or by a change of Ca2+ content in the slices. Incubation with 1 mM ethacrynic acid or mersalyl depressed Mg2+ influx and stimulated Mg2+ efflux, p-chloromercuribenzoic acid (5 X 10(-4) M) had a similar effect and furosemide had no effect on Mg2+ transport. These results suggest that Mg2+ influx is mediated by an energy-dependent process which is dissociated from ouabain-sensitive Na+ transport and Ca2+ flux. Sulfhydryl groups may be involved in the process of Mg2+ influx.

Animals↗

Extracellular calcium effects on cell viability and thiol homeostasis.

Studies of chemically induced cell injury and death, which have used as model systems freshly isolated rat hepatocytes and hepatocytes in culture, are discussed. An important model uses the omission of Ca2+ from the medium during rat hepatocyte incubations. Ca2+ omission induces an intense oxidative stress within hepatocytes incubated in a 95% O2 + 5% CO2 atmosphere. The relationship of calcium homeostasis to the parameters of oxidative stress is important to understanding the progression from reversible to irreversible injury. In the Ca2+ omission model, the vitamin E (Vit. E) content of hepatocytes is important for the prevention of cell injury. Recent studies with rat hepatocytes show that ruthenium red (RR) and La3+, which block Ca2+ translocation through the mitochondrial uniport, can prevent malondialdehyde (MDA) formation, reduced glutathione (GSH), and protein-SH loss, Vit. E loss, and LDH leakage induced by Ca2+ omission from the incubation medium. Ca2+ omission promoted a marked loss of mitochondrial transmembrane potential (delta phi) that was prevented by RR, EGTA, Vit. E, and desferrioxamine. The absence of extracellular Ca2+ may cause mitochondrial Ca2+ cycling that contributes to the observed oxidative stress, resultant loss of cell viability, and protein thiol homeostasis. Chemical agents including a glutathione-depleting agent, ethacrynic acid, and a redox cycling agent, adriamycin, increase the loss of cell viability caused by a Ca2(+)-free medium, but they have some additional effects on cellular processes. The demise of cell viability by the agent is also preventable by Vit. E supplementation. Ca2+ has a role in cell injury that appears to uniquely involve mitochondrial homeostasis.

Animals↗

Probable loop diuretic-induced pancreatitis in a sulfonamide-allergic patient.

OBJECTIVE: To report the case of a patient with a prior allergy to a sulfonamide antibiotic who subsequently developed the same reaction when administered various loop diuretics. CASE SUMMARY: A 57-year-old female with cardiomyopathy and "sulfa" (trimethoprim/sulfamethoxazole) allergy documented as pancreatitis presented with symptoms consistent with pancreatitis after use of furosemide. She subsequently developed similar symptoms after multiple rechallenges with various loop diuretics including furosemide, bumetanide, and torsemide. The patient was placed on ethacrynic acid until she was desensitized to furosemide. She had been receiving oral furosemide for 5 months at the time of this report, with no complications. According to the Naranjo probability scale, this reaction was probable. DISCUSSION: Reactions associated with arylamine sulfonamide-containing antibiotics have been commonly reported; however, cross-reactions with non-arylamine sulfonamide-containing medications have been rare. The time delay by which symptoms of pancreatitis presented following administration of loop diuretics suggests an immunologic pathway. In addition, while cases of loop diuretic-induced pancreatitis, including furosemide, have been published, the allergic manifestations with both sulfonamide antibiotics and non-antibiotics in our patient suggest possible cross-reactivity between these 2 drug classes. CONCLUSIONS: The mechanism by which loop diuretics induce pancreatitis appears to be via an immunologic pathway. While the true correlation remains unknown, allergic cross-reactivity may occur between sulfonamide antibiotics and non-antibiotics, such as loop diuretics. Torsemide appears to also be a part of a long list of agents that can cause pancreatitis.

Cardiomyopathies↗

Efficacy and safety of a furosemide continuous infusion following cardiac surgery.

OBJECTIVE: To review the literature regarding the efficacy and safety of continuous intravenous infusion of loop diuretics following cardiac surgery. DATA SOURCES: Articles were identified through a MEDLINE search (1966-March 2006) using the key words furosemide, bumetanide, torsemide, ethacrynic acid, loop diuretics, continuous infusions, intravenous infusions, surgery, cardiac surgery, cardiovascular surgery, and thoracic surgery. Search results were limited to studies in human subjects published in English. Additional references were identified through review of the bibliographies of the articles cited. STUDY SELECTION AND DATA EXTRACTION: All clinical trials and observational reports identified that evaluated or described the efficacy and/or safety of a continuous infusion of a loop diuretic in adult or pediatric patients who had undergone cardiac surgery were included in this review. DATA SYNTHESIS: Loop diuretics are often used to promote diuresis following cardiac surgery. Studies in patients who have undergone cardiac surgery have demonstrated that a more consistent and sustained diuresis is produced by a continuous infusion of furosemide compared with intermittent bolus doses of furosemide. However, there does not appear to be a significant difference in total urine output or change in serum electrolyte levels when furosemide is administered as a continuous infusion compared with intermittent bolus doses. CONCLUSIONS: A continuous infusion of furosemide is an effective and safe method of diuresis in patients undergoing cardiac surgery.

Arrhythmias, Cardiac↗

Combined effects of cadmium and nickel on testicular xenobiotic metabolizing enzymes in rats.

When male rats were given a single dose of cadmium (Cd) (3.58 mg CdCl2 x H2O/kg, i.p.) 72 hr prior to sacrifice, the testicular 7-ethoxyresorufin O-deethylase (EROD) and glutathione S-transferase (GST) activities toward the substrates 1-chloro-2,4-dinitrobenzene (CDNB), 1,2-dichloro-4-nitrobenzene (DCNB), ethacrynic acid (EAA), 1,2-epoxy-3-(p-nitrophenoxy)-propane (EPNP), and cumene hydroperoxide (CHPx) decreased significantly as compared to controls. Cd also inhibited reduced glutathione (GSH) level while increasing the lipid peroxidation (LP) level significantly. When the animals were given a single dose of nickel (Ni) (59.5 mg NiCl2 x 6H2O/kg, i.p.) 16 hr prior to sacrifice, significant decreases were observed in EROD and GST activities toward CDNB, EAA, EPNP, and CHPx, and GSH level. No significant alterations were noted in DCNB GST activity and LP level by Ni. For the combined treatment, rats received the single dose of Ni 56 hr after the single dose of Cd and were killed 16 hr later. In these animals, lesser depressions were observed on EROD activity and LP level than those of Cd alone. The combination of metals significantly inhibited GST activities and GSH level but not to a greater degree than noted by Cd or Ni alone. Plasma testosterone levels of Cd-, Ni-, and combination-treated rats decreased significantly compared to controls. The strongest depression was achieved by Cd alone. Cd, both alone and in combination with Ni, increased the tissue Ni uptake significantly. Ni, however, did not produce such an effect on the tissue uptake of Cd in either case. Cd treatment caused interstitial edema and coagulation necrosis in seminiferous tubules and also caused fibrinoidal necrosis in vascular endothelium. Ni treatment did not produce any pathological testicular alterations compared to controls. Combined treatment produced fewer pathological alterations (i.e., only interstitial edema) than that of Cd treatment. These results reveal that the combination of Cd and Ni does nothave a synergistic effect on testicular xenobiotic metabolizing enzymes, and in contrast, Ni has an ameliorating effect on pathological disturbances caused by Cd alone in the rat testis.

Animals↗

Glutathione S-transferase of the malarial parasite Plasmodium falciparum: characterization of a potential drug target.

Glutathione S-transferases (GSTs), which occur abundantly in most organisms, are essentially involved in the intracellular detoxification of numerous substances including chemotherapeutic agents, and thus play a major role in the development of drug resistance. A gene encoding a protein with sequence identity of up to 37% with known GSTs was identified on chromosome 14 of the malarial parasite Plasmodium falciparum. It was amplified using gametocyte cDNA and expressed in Escherichia coli as a hexahistidyl-tagged protein of 26 kDa subunit size. The homodimeric enzyme (PfGST) was found to catalyse the glutathione (GSH)-dependent modification of 1-chloro-2,4-dinitrobenzene and other typical GST substrates such as o-nitrophenyl acetate, ethacrynic acid, and cumene hydroperoxide. The Km value for GSH was 164+/-20 microM. PfGST was inhibited by cibacron blue (Ki=0.5 microM), S-hexylglutathione (Ki=35 microM), and protoporphyrin IX (Ki=10 microM). Hemin, a most toxic compound for parasitised erythrocytes, was found to be an uncompetitive ligand of PfGST with a Ki of 6.5 microM. Based on the activity of PfGST in extracts of P. falciparum, the enzyme represents 1 to 10% of cellular protein and might therefore serve as an efficient in vivo buffer for parasitotoxic hemin. Destabilising ligands of GST are thus expected to be synergistic with the antimalarial drug chloroquine, which itself was found to be a very weak inhibitor of PfGST (IC50>200 microM). X-ray quality crystals of PfGST (250x200x50 microm) will serve as starting point for structure-based drug design.

Amino Acid Sequence↗

Glutathione S-transferases as emerging therapeutic targets.

Glutathione S-transferases (GST) represent a large family of Phase II detoxification enzymes widely expressed in animals and plants. These enzymes catalyse the conjugation of glutathione with some endogenous molecules and a broad range of exogenous substrates including various anticancer drugs. Due to high expression of GSTs in tumours when compared to normal tissues and their high level in plasma from cancer patients, these enzymes are considered to be cancer markers. Their involvement in resistance to anticancer drugs and an inverse correlation between expression and prognosis in many tumours provided a rationale for the design of inhibitors and prodrugs to enhance therapeutic index. The first generation of GST inhibitors included ethacrynic acid and showed promising potentiating activity in vitro but lack of isoenzyme specificity and diuretic side effects restricted clinical use. Novel GST inhibitors include glutathione analogues and demonstrate better specificities with fewer limiting toxicities. One lead compound is a potent inhibitor of the GSTP1-1 isoform in both cell lines and animal models. A GSTP1-1 activated prodrug has also been developed. Testing of the preclinical and clinical efficacy of these agents is presently in progress. Their rational design provides a promising new approach to targeting tumour-specific characteristics in a manner consistent with improving therapeutic index.

Journal Article↗

Reported medication use in the neonatal intensive care unit: data from a large national data set.

OBJECTIVES: The objectives were (1) to identify the drugs reported most commonly during NICU care, (2) to examine how different methods of documenting drug use could influence prioritization of drugs for future research aimed at evaluating safety and efficacy, (3) to describe the demographic differences in the population samples for some specific medications, (4) to identify which reported medications are used for patient populations with >20% mortality rates, and (5) to examine how reports of drug use change over time. METHODS: A retrospective review of a large national data set was performed. RESULTS: The 10 medications reported most commonly for the NICU were ampicillin, gentamicin, ferrous sulfate, multivitamins, cefotaxime, caffeine citrate, furosemide, vancomycin, surfactant, and metoclopramide. Medications used for patient populations with >20% mortality rates included amphotericin, clonazepam, dobutamine, epinephrine, ethacrynic acid, insulin, lidocaine, metolazone, milrinone, inhaled nitric oxide, nitroglycerin, octreotide, pancuronium, phenytoin, sodium nitroprusside, sodium polystyrene sulfonate (Kayexalate), tris-hydroxymethylaminomethane acetate buffer, and tolazoline. Several of these drugs (eg, amphotericin B and bumetanide) were used primarily for extremely premature neonates, and this usage might explain the high mortality rates for the population of neonates treated with these medications. Other medications (clonazepam, milrinone, inhaled nitric oxide, and phenytoin) were used primarily for near-term and term infants. The explanation for the high mortality rates for these neonates is less clear and may be related primarily to the severity of illness for which the medications are used. Utilization rates for several different medications (eg, cisapride, metoclopramide, and dexamethasone) changed by >50% during the past 5 years. CONCLUSIONS: Data reported here are the first from a large national data set on the use of different medications for neonates admitted for intensive care and should be helpful in establishing priority agendas for future drug studies in this population.

Drug Utilization↗

Electrophysiologic characterization of an organic anion transporter cloned from winter flounder kidney (fROAT).

The two-electrode voltage clamp technique was used to demonstrate translocation of p-aminohippurate (PAH) and related compounds such as loop diuretics in Xenopus laevis oocytes expressing the renal organic anion transporter from winter flounder kidney (fROAT). In fROAT-expressing oocytes, PAH (0.1 mM) induced a depolarization of 4.2 +/- 0.4 mV and at a holding potential of -60 mV an inward current of -22.6 +/- 3.5 nA. PAH-induced current and the current calculated from [3H]-PAH uptake were of similar magnitude. Depolarization, inward current, and current-to-uptake relation indicated exchange of the monovalent PAH with a divalent anion, possibly alpha-ketoglutarate (alpha-KG), causing net efflux of one negative charge. The kinetic analysis of PAH-induced currents revealed that translocation is dependent on membrane potential, saturable with an apparent Km of 58 +/- 8 microM, and sensitive to probenecid and furosemide. In contrast to probenecid and furosemide, the loop diuretics bumetanide, ethacrynic acid, and tienilic acid and the nephrotoxic mycotoxin ochratoxin A elicited inward currents indicating translocation through fROAT. Substrate-dependent currents provide a tool to elucidate the structure/function relationship of the renal organic anion transporter.

Animals↗

In vitro degradation of hexanitrohexaazaisowurtzitane (CL-20) by cytosolic enzymes of Japanese quail and the rabbit.

Hexanitrohexaazaisowurtzitane (CL-20) is a polycyclic nitramine explosive and propellant, currently being considered as a potential replacement for existing cyclic nitramine explosives. Earlier studies have provided evidence suggestive of adverse liver effects in adult Coturnix spp. exposed to CL-20, yet analysis of tissue samples (plasma, liver, brain, heart, or spleen) indicated that CL-20 was not detectable in these treated animals. The present study was conducted to identify and purify the enzymes capable of CL-20 biotransformation. Results indicate that the hepatic biotransformation of CL-20 in vitro was inhibited by ethacrynic acid (93%) and by the glutathione (GSH) analogue S-octylglutathione (80%), suggesting the involvement of glutathione-S-transferase (GST). Partially purified cytosolic alpha- and mu-type GST (requiring presence of GSH as a cofactor) from quail and rabbit liver was capable of CL-20 biotransformation. The degradation of CL-20 (0.30 +/- 0.05 and 0.40 +/- 0.02 nmol/min/mg protein for quail and rabbit, respectively) was accompanied with the formation of nitrite and consumption of GSH. Using liquid chromatography/mass spectrometry, we detected two intermediates, that is, open-ring, monodenitrated GSH-conjugated CL-20 biotransformation product with the same deprotonated molecular mass ion at 699 Da, suggesting isomeric forms of the intermediate metabolites. Identity of the conjugated metabolites was confirmed by using ring-labeled [15N]CL-20 and the nitro group-labeled [15NO2]CL-20. These data suggest that the in vitro biotransformation of CL-20 by GST under the conditions tested may be a key initial step in the in vivo degradation of CL-20 in the quail and resulted in the formation of more biologically reactive intermediates than the parent compound. These data will aid in our understanding of the biotransformation processes of CL-20 in vivo.

Amino Acid Sequence↗