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PubMed2000

Diagnostic value of urinary alanine aminopeptidase and N-acetyl-beta-D-glucosaminidase in comparison to alpha 1-microglobulin as a marker in evaluating tubular dysfunction in glomerulonephritis patients.

To estimate the diagnostic value of tubular parameters, the urinary alanine aminopeptidase (AAP), N-acetyl-beta-D-glucosaminidase (NAG) and the alpha(1)-microglobulin (a1M) of 150 patients with histologically proven glomerulonephritis (GN) were determined. In addition, the reabsorption rate of the proximal tubule and the fractional excretion of sodium, the free water clearance and the renal function were assessed by inulin and p-aminohippurate (PAH) clearance. Compared to healthy controls, urinary AAP, NAG and a1M were found significantly elevated in GN patients. Morphological tubular changes were confirmed by significant differences in urinary laboratory parameters. In patients with tubular atrophy, the diagnostic sensitivity and specificity were calculated as follows: AAP (0.94/0.35), NAG (0.75/0.59) and a1M (0.73/0.52). In patients showing tubular protein droplets, the values were 0.90/0.17 for AAP, 0.78/0.76 for NAG and 0.84/0.74 for a1M and in patients with interstitial fibrosis, the values were AAP (0.95/0.35), NAG (0.75/0. 46) and a1M (68/0.38). Urinary AAP, NAG and a1M reflect histologically proven tubulus alteration in GN, although in most cases, the renal function is still intact. AAP indicates very early tubular impairment and, in some cases, AAP is elevated although NAG and a1M are still within normal ranges. We suggest that the enzyme activities are useful in the diagnostics of early stages of the disease.

Acetylglucosaminidase↗
PubMed1996

The general L-amino acid permease of Rhizobium leguminosarum is an ABC uptake system that also influences efflux of solutes.

A general L-amino acid permease (Aap) from the ABC transporter family, encoded by four genes (aapJ, Q, M, P), has been cloned and characterized in Rhizobium leguminosarum. It transports a wide range of L-amino acids but has a preference for those with polar side-chains. A single binding protein of broad specificity (AapJ) is required for transport of all solutes. Unusually for an ABC transporter, Aap has both high affinity for and supports high rates of solute uptake. Genes for putative amino acid permeases with broad specificity for amino acids also exist in Escherichia coli and probably in Pseudomonas fluorescens, although the permease from E. coli does not appear to be expressed. Aap is an active uptake system that also affects the efflux of a broad range of amino acids. Efflux can be measured both as the loss of an intracellular amino acid after the addition of an excess of a homologous or heterologous amino acid, and as excretion of intracellularly synthesized glutamate. Mutation of Aap prevented efflux of intracellular amino acids caused by the addition of an extracellular heterologous amino acid, while overexpression increased the rates of such efflux. Furthermore, excretion of glutamate synthesized inside the cell was reduced by 76% in an aap strain. All four gene products, including the binding protein (AapJ), appear to be needed for efflux. Aap from R. leguminosarum expressed in E. coli also promoted efflux on addition of an extracellular heterologous amino acid. These results indicate either that Aap regulates an efflux channel/transporter or that solute has access to the translocation pathway of Aap from both sides of the membrane.

ATP-Binding Cassette Transporters↗
PubMedDate not supplied

Influence of diuresis on enzymuria.

Urinary excretion of renal brush border enzymes may serve as an early marker of renal injury. However, the distinction between physiological and pathological levels remains controversial, since enzymuria is affected by physiological parameters. To clarify the influence of diuresis, we investigated the urinary excretion of alanine-aminopeptidase (AAP; EC 3.4.11.2) as function of diuretic state. 17 healthy volunteers of both sexes were subjected to protocols with sudden or prolonged water load preceded and followed by a thirst period. Urinary excretion of AAP was measured using an enzyme kinetic assay. As expected AAP excretion increased with urine flow, the increments diminished yielding an overall excretion pattern that resembled saturation kinetics. This function is described by a mathematical model. This model assumes, that AAP is released in proximal tubules at a constant rate and reabsorbed or inactivated in the distal tubule and collecting duct. Non-linear fits of the model equation to our data allowed two parameters, chi and mu, to be defined. Chi describes the rate of AAP release independent of urinary flow, and mu the ratio of distal tubular reabsorption or inactivation. If a substrate is not reabsorbed at all, mu approximates zero. Since mu fitted for AAP differed significantly from zero, this indicates reabsorption or inactivation of AAP in the distal nephron. Therefore, our study supports the theory of flow-dependent reabsorption or inactivation of AAP in the distal nephron.

Adult↗
PubMed2004

Pathophysiological role of poly(ADP-ribose) polymerase (PARP) activation during acetaminophen-induced liver cell necrosis in mice.

DNA fragmentation in hepatocytes occurs early after acetaminophen (AAP) overdose in mice. DNA strandbreaks can induce excessive activation of poly(ADP-ribose) polymerases (PARP), which may lead to oncotic necrosis. Based on controversial findings with chemical PARP inhibitors, the role of PARP-1 activation in AAP hepatotoxicity remains unclear. To investigate PARP-1 activation and evaluate a pathophysiological role of PARP-1, we used both PARP inhibitors (3-aminobenzamide; 5-aminoisoquinolinone) and PARP gene knockout mice (PARP-/-). Treatment of C3Heb/FeJ mice with 300 mg/kg AAP resulted in DNA fragmentation and alanine aminotransferase (ALT) release as early as 3 h, with further increase of these parameters up to 12 h. Few nuclei of hepatocytes stained positive for poly-ADP-ribosylated nuclear proteins (PAR) as indicator for PARP-1 activation at 4.5 h. However, the number of PAR-positive cells and staining intensity increased substantially at 6 and 12 h. Pretreatment with 500 mg/kg 3-aminobenzamide before AAP attenuated hepatic glutathione depletion and completely eliminated DNA fragmentation and liver injury. Delayed treatment several hours after AAP was still partially protective. On the other hand, liver injury was not attenuated in PARP-/- mice compared to wild-type animals. Similarly, the specific PARP-1 inhibitor 5-aminoisoquinolinone (5 mg/kg) was not protective. However, 3-aminobenzamide attenuated liver injury in WT and PARP-/- mice. In summary, PARP-1 activation is a consequence of DNA fragmentation after AAP overdose. However, PARP-1 activation is not a relevant event for AAP-induced oncotic necrosis. The protection of 3-aminobenzamide against AAP-induced liver injury was due to reduced metabolic activation and potentially its antioxidant effect but independent of PARP-1 inhibition.

Acetaminophen↗
PubMed2002

Peroxynitrite is a critical mediator of acetaminophen hepatotoxicity in murine livers: protection by glutathione.

Acetaminophen (AAP) overdose causes formation of nitrotyrosine, a footprint of peroxynitrite, in centrilobular hepatocytes. The importance of peroxynitrite for the pathophysiology, however, is unclear. C3Heb/FeJ mice were treated with 300 mg/kg AAP. To accelerate the restoration of hepatic glutathione (GSH) levels as potential endogenous scavengers of peroxynitrite, some groups of animals received 200 mg of GSH/kg i.v. at different time points after AAP. AAP induced severe liver cell damage at 6 h. Total liver and mitochondrial glutathione levels decreased by >90% at 1 h but recovered to 75 and 45%, respectively, of untreated values at 6 h after AAP. In addition, the hepatic and mitochondrial glutathione disulfide (GSSG) content was significantly increased over baseline, suggesting a mitochondrial oxidant stress. Moreover, centrilobular hepatocytes stained for nitrotyrosine. Treatment with GSH at t = 0 restored hepatic GSH levels and completely prevented the mitochondrial oxidant stress, peroxynitrite formation, and liver cell injury. In contrast, treatment at 1.5 and 2.25 h restored hepatic and mitochondrial GSH levels but did not prevent the increase in GSSG formation. Nitrotyrosine adduct formation and liver injury, however, was substantially reduced. GSH treatment at 3 h after AAP was ineffective. Similar results were obtained when these experiments were repeated with glutathione peroxidase-deficient animals. Our data suggest that early GSH treatment (t = 0) prevented cell injury by improving the detoxification of the reactive metabolite of AAP. Delayed GSH treatment enhanced hepatic GSH levels, which scavenged peroxynitrite in a spontaneous reaction. Thus, peroxynitrite is an important mediator of AAP-induced liver cell necrosis.

Acetaminophen↗
PubMed2003

Scavenging peroxynitrite with glutathione promotes regeneration and enhances survival during acetaminophen-induced liver injury in mice.

Acetaminophen (AAP) overdose causes formation of peroxynitrite in centrilobular hepatocytes. Treatment with glutathione (GSH) after AAP accelerated recovery of mitochondrial GSH levels, which scavenged peroxynitrite and protected against liver injury at 6 h. The objective of this investigation was to evaluate whether GSH treatment has a long-term protective effect against AAP-induced injury and whether it promotes liver regeneration. AAP (300 mg/kg) induced severe centrilobular necrosis and increased plasma alanine aminotransferase (ALT) activities (24 h: 3680 +/- 320 U/liter) in fasted C3Heb/FeJ mice. Only 53% of the animals survived for 24 h. Hepatic glutathione levels were still suppressed by 62% at 24 h compared with untreated controls (19.7 +/- 2.6 micromol/g). Glutathione disulfide (GSSG) concentrations were elevated by 455% compared with controls (74 +/- 3 nmol/g liver). Treatment with GSH at 1.5 h after AAP treatment attenuated liver necrosis and plasma ALT activities by 62 to 66% at 24 h. All animals survived up to 7 days. The hepatic GSH content recovered to control values; however, the GSSG levels were still elevated at 48 h (252 +/- 26 nmol/g). Expression of proliferating cell nuclear antigen (PCNA) and cell cycle proteins cyclin D1 and p21 were not detectable in controls or after AAP alone. Treatment with GSH after AAP induced expression of cyclin D1, p21, and PCNA (12-48 h). Thus, GSH treatment after AAP provided long-term hepatoprotection and promotes progression of cell cycle activation in hepatocytes.

Acetaminophen↗
PubMed2004

Enhancement of acetaminophen cytotoxicity in selenium-binding protein-overexpressed COS-1 cells.

The role of selenium-binding protein (SeBP), which has a high ability to associate with acetaminophen (AAP), on the cytotoxicity of AAP was studied. To clarify this issue, we examined the cytotoxic effect of AAP using COS cells stably expressing SeBP. Expression of SeBP enhanced the susceptibility of the cells to AAP-induced cytotoxicity. Several clones of SeBP-expressed COS cells were obtained, and they exhibited different degrees of susceptibility toward AAP. It was found that there is an inverse correlation between the expression level and the cell viability (r=-0.872). On the other hand, no increase in toxicity was observed in the SeBP-expressed cells treated with N-acetyl-p-quinone imine (NAPQI), which is an active metabolite of AAP. These results show that SeBP is an important factor in AAP hepatotoxicity. Moreover, our data suggest that the toxic mechanism of AAP differs from that of NAPQI.

Acetaminophen↗
PubMed2004

Using existing population-based data sets to measure the American Academy of Pediatrics definition of medical home for all children and children with special health care needs.

OBJECTIVE: National health goals include ensuring that all children have a medical home. Historically, medical home has been determined by the presence of a usual or primary source of care, such as a pediatrician or a family physician. More recent definitions expand on this simplistic notion of medical home. A definition of medical home set forth by the American Academy of Pediatrics (AAP) includes 7 dimensions and 37 discrete concepts for determining the presence of a medical home for a child. Standardized methods to operationalize these definitions for purposes of national, state, health plan, or medical practice level reporting on the presence of medical homes for children are essential to assessing and improving health care system performance in this area. The objective of this study was to identify methods to measure the presence of medical homes for all children and for children with special health care needs (CSHCN) using existing population-based data sets. METHODS: Methods were developed for using existing population-based data sets to assess the presence of medical homes, as defined by the AAP, for children with and without special health care needs. Data sets evaluated included the National Survey of Children With Special Health Care Needs, the National Medical Expenditures Panel Survey, the Consumer Assessment of Health Plans Study Child Survey (CAHPS), and the Consumer Assessment of Health Plans Study Child Survey--Children With Chronic Conditions (CAHPS-CCC2.0H). Alternative methods for constructing measures using existing data were compared and results used to inform the design of a new method for use in the upcoming National Survey of Children's Health. Data from CAHPS-CCC2.0H are used to illustrate measurement options and variations in the overall presence of medical homes for children across managed health care plans as well as to evaluate in which areas of the AAP definition of medical home improvements may be most needed for all CSHCN. RESULTS: Existing surveys vary in their coverage of concepts included in the AAP definition of medical home and, therefore, in their capacity to evaluate medical home for children with and without special health care needs. Using data from CAHPS-CCC2.0H, the overall proportion of children who were enrolled in managed care health plans and met criteria for having a medical home varied from 43.9% to 74% depending on the specific scoring method selected for these items. Wide variations across health plans were observed and were most prominent in the areas of "accessible care" and "comprehensive care." Performance was uniformly poorest in the area of "coordinated care" and for CSHCN. Although children with a personal doctor or nurse were more likely to meet the AAP criteria for having a medical home, simply having a personal doctor or nurse was not highly predictive of whether a child experienced the other core qualities of a medical home (positive predictive value: .50; negative predictive value: .59). CONCLUSIONS: Despite differences across existing surveys and gaps in concepts represented, we believe that the AAP definition of medical home can be well represented by the small subset of concepts represented in the National Survey of Children With Special Health Care Needs and the CAHPS-CCC2.0H. A less comprehensive yet still worthwhile measure is possible using the Medical Expenditures Panel Survey. The varying degrees of empirical evidence and consensus for each of the AAP definition domains for medical home suggest the need for constructing measures that also vary in terms of criteria for determining that a child does or does not have a medical home. In addition to a simple "yes or no," or rate-based, measure, a continuous medical "homeness" score that places a child or group of children on a continuum of medical "homeness" is also valuable. Findings indicate that health plans have an important role to play in ensuring medical homes for children in addition to medical practices and those who set policies that guide the design and delivery of health care for children. Oven. Overall, using existing population-based data, a measure of medical home that is aligned with the AAP definition is feasible to include in the annual National Healthcare Quality Report, in state reports on the quality of Medicaid, State Children's Health Insurance Program, and Title V programs as well as to evaluate performance on the Healthy People 2010 objectives and the President's New Freedom Initiative.

Child↗
PubMedDate not supplied

Aortic anastomotic pseudoaneurysms: US, CT, MR, and angiography.

Correlation of imaging and anatomic findings in seven men with abdominal aortic graft prostheses (four "end-to-end" anastomoses and three "end-to-side" anastomoses) was done to compare the value of different imaging modalities in detecting postoperative complications, especially aortic anastomotic pseudoaneurysms (AAPs). In all cases, angiographic and CT studies were carried out. In six patients ultrasound and MR examinations were also performed. Anatomic verification was obtained by surgery in six patients and autopsy in one case. Five patients had an AAP (four at surgery and one at autopsy), one had a true abdominal aortic aneurysm above the anastomosis, and one a nondetectable abnormality of the aortic suture line. Digital subtraction angiography diagnosed one of five AAPs, missed the true aneurysm in the sixth patient, and was normal in the patient without any aneurysm. Computed tomography correctly diagnosed the five AAPs and the true aneurysm and was normal in the last patient. Ultrasound correctly diagnosed the AAPs in three of four patients, incorrectly diagnosed an AAP in the patient who had the true aneurysm, and was normal in the patient without any aneurysm. Magnetic resonance diagnosed four of four AAPs and the true aneurysm and was normal in the last patient. Computed tomography seems to be the best imaging modality with which to diagnose and evaluate an aortic AAP in patients with aortoiliofemoral graft prosthesis.

Aged↗
PubMed1995

Ketoconazole inhibits acetaminophen-induced hepatotoxicity in mice.

OBJECTIVE: To investigate the effect of ketoconazole on acetaminophen (AAP)-induced hepatotoxicity in mice. MATERIALS AND METHODS: Mice were given AAP intragastrically (300 mg/kg) and treated with ketoconazole (100 mg/kg intraperitoneally) or saline either 30 min before or 2-3 h after AAP administration. Mortality was recorded for 48 h, during which all mice given saline either died or recovered fully. Serum alanine and aspartate transaminase levels were determined 24 h after administration of AAP. Prostaglandin E2, thromboxane A2 and leukotriene C4 production was determined 6 h after AAP administration in the supernatants from the short-term culture of liver fragments by radioimmunoassay. RESULTS: Ketoconazole significantly decreased mortality and transaminase levels when given to mice either 30 min before or 2 h after AAP. Liver fragments from mice with AAP hepatitis produced greater quantities of prostaglandin E2, thromboxane A2 and leukotriene C4 than fragments from normal liver. Pretreatment of mice with ketoconazole or its addition to liver fragments ex vivo further increased the production of prostaglandin E2 and reduced the production of thromboxane A2. The effect of ketoconazole on leukotriene C4 synthesis was different in vivo (synthesis stimulation) from in vitro (synthesis inhibition). CONCLUSION: The protective effect of ketoconazole in AAP hepatitis is most probably mediated by modulation of eicosanoid synthesis by liver cells.

Acetaminophen↗
PubMed1996

Acetaminophen plasma level after oral administration in liver cirrhotic patients suffering from schistosomal infection.

Hepatosplenic schistosomal infection is a common parasitic liver disease in Egypt, resulting in the formation of granuloma followed by fibrosis which leads to the chronic liver disease. Plasma level of acetaminophen (AAP) and its glucuronide and sulfate metabolites after oral administration at a dose of 1 g was determined in liver-cirrhotic younger (9 - 25 years old) and elderly patients (45 - 65 years old) suffering from schistosomal infection. These levels of AAP and its metabolites in patient groups were compared with those in corresponding healthy subject groups. Examinations for participants in the present study by physicians indicated the more severe cirrhosis in elderly patients compared to younger patients and the formation of collateral circulation and the renal insufficiency in elderly patients. The elimination of AAP from plasma was significantly prolonged in both younger and elderly patient groups. In elderly patients plasma concentration of AAP in early stage (before the time to reach Cmax) was significantly higher, indicating the partial avoidance of first-pass metabolism due to the formation of hepatic shunt pathway. Plasma concentration of AAP-glucuronide was greatly decreased in both patient groups, whereas no significant difference in the plasma concentration of AAP-sulfate compared to those in corresponding healthy subject groups. These results will suggest that with repeated dosing of AAP special care must be taken in schistosomal patients since the elimination of AAP from plasma is remarkably reduced.

Acetaminophen↗
PubMed1996

Rapid induction of hepatocyte growth factor mRNA after administration of gomisin A, a lignan component of shizandra fruits.

Gomisin A (Go), a lignan component of shizandra fruits, protects the liver from injury by acetaminophen (AAP). One of its possible mechanisms is supposed to be related to the suppression of lipid peroxidation. Since hepatocyte growth factor (HGF) was reported to prevent hepatotoxin-induced liver damage, we tested HGF as the intermediary of Go effects. Simultaneous analyses of HGF mRNA expression and liver histology in rats were performed at 6 and 24 hr after treatment with AAP, Go or both. HGF mRNA rapidly expressed at 6 hr after Go treatment, while no HGF mRNA was observed at 6 hr after AAP treatment. Induction of HGF mRNA at 24 hr was observed after treatment with AAP or AAP plus Go. Histological findings indicate that massive necrosis and vacuolization in the liver of rats treated with both AAP and Go were reduced in comparison with rats treated with AAP only. These data suggest that Go rapidly induces HGF mRNA through different mechanisms from AAP-induced liver injury.

Alanine Transaminase↗
PubMed1997

Electrophoresis of DNA sequencing fragments at elevated temperature in capillaries filled with poly(N-acryloylaminopropanol) gels.

The performance of poly(N-acryloylaminopropanol) (poly AAP) gel columns, proved to be stable during electrophoresis at elevated temperature, was investigated. The column manufacturing procedure included the preparation of a coating of the inner wall of the fused silica capillary column with linear poly(AAP). Then, a mixture of the AAP monomer, the cross-linker dihydroxyethylenebisacrylamide (DHEBA) and linear poly(AAP) was introduced into the column and in situ polymerized (for preparation of linear gel columns, the addition of DHEBA was omitted). The poly(AAP) columns were first evaluated by electrophoresis of oligonucleotides at room temperature and at 50 degrees C, utilizing 260 nm UV-absorbance detection. In a further evaluation of column performance, samples of T-terminated DNA Sanger fragments from the bacteria Moraxella were separated at 200 V/cm electrical field strength, utilizing a 488 nm argon ion laser and a confocal optical setup for laser-induced fluorescence (LIF) detection. A temperature increase from 25 degrees C to 50 degrees C effectively released a compression of DNA bands. However, for cross-linked poly(AAP) gel columns, the elevated temperature resulted in a considerable reduction of the DNA sequence reading length. When a linear poly(AAP) column was utilized, no detrimental effect of elevated temperature on the separation could be observed.

Acrylic Resins↗
PubMed2004

Hepatoprotective and antioxidant effects of Alnus japonica extracts on acetaminophen-induced hepatotoxicity in rats.

The stem bark of the Betulaceae plant Alnus japonica, which is indigenous to Korea, has been used as a popular folk medicine for hepatitis and cancer. In this study, the antioxidant activity of the crude extract and the hepatoprotective activities on acetaminophen (AAP)-induced toxicity in the rat liver were evaluated. We investigated the effect of the methanol (AJM) and solvent fracton of the stem bark of Alnus japonica (AJ) on AAP-induced hepatotoxicity in rats. In rat hepatocyte culture, pretreatment with AJM (50, 100, 150 and 200 microg/ml) significantly decreased the cytotoxicity of AAP in a dose-dependent manner. The pretreated with EtOAc and BuOH fraction led to an increase in free radical scavenging activity and a decrease in inhibition of lipid peroxidation, both superoxide dismutase and catalase prevent the hepatotoxicity by AAP in the treatment of A. japonica fraction. We conclude that AJ is an important antioxidant in AAP-induced live hepatotoxicity and that extract of AJM plays a hepatoprotective effects in the against AAP-induced cytotoxicity in cultured rat hepatocytes in vitro. Pending more evaluation for safety and efficacy, AJ can potentially be used in mitigating AAP-induced hepatotoxicity.

Acetaminophen↗
PubMed1994

A new synthetic antiarrhythmic peptide reduces dispersion of epicardial activation recovery interval and diminishes alterations of epicardial activation patterns induced by regional ischemia. A mapping study.

Common antiarrhythmic agents affect ionic membrane channels and thereby alter cellular electrical activity. Since this accounts for the proarrhythmic effects as well we tried to find new substances with different profiles of actions. A new antiarrhythmic peptide, H2N-Gly-Ala-Gly-4 Hyp-Pro-Tyr-CONH2 (AAP 10), was synthetized using the Fmoc-strategy. This peptide was analyzed for its electrophysiological profile of action in normal isolated rabbit hearts perfused according to the Langendorff technique either under control conditions or after induction of a regional ischemia. For this purpose 256 channel epicardial mapping was employed allowing the determination of the timepoints of activation at each electrode thus identifying the origins of epicardial activation (socalled breakthrough-points, BTP). Epicardial spread of activation was then described mathematically by activation vectors which gave direction and velocity of the epicardial activation wave at each electrode. Single heart beats were analyzed under control conditions and under treatment with AAP 10 or under regional ischemia with or without AAP 10-pretreatment (10(-8) mol/l). We calculated the percentage of similar vectors (VEC) with unaltered direction (deviation < or = 5 degrees) and the percentage of identical breakthroughpoints (deviation < or = 1 mm) compared to control conditions. In addition, apparent epicardial velocities, total activation time of a given region and activation-recovery interval (ARI) as well as dispersion of ARI (i.e. standard deviation of ARI) and distribution of ARI were analyzed. Under control conditions treatment with AAP 10 (10(-10) to 3 x 10(-7) mol/l) led to a significant decrease in ARI-dispersion without alteration of any of the other parameters under investigation. Left ventricular regional ischemia resulted in a marked alteration of the activation patterns (a significant decrease in vectorfield- and breakthroughpoint-similarity) which could be significantly inhibited by pretreatment with AAP 10. In addition, we found that AAP 10 depressed the increase in ARI-dispersion during the first minutes of ischemia and accelerated normalization of ARI-dispersion during reperfusion. In additional experiments, it could be shown that AAP 10 did not alter action potential duration, maximum dU/dt, amplitude or resting membrane potential of isolated guinea pig muscles using a common intracellular action potential recording technique.(ABSTRACT TRUNCATED AT 400 WORDS)

Action Potentials↗
PubMed1986

Effect of N-nitrosamines carcinogenic for oesophagus on O6-alkyl-guanine-DNA-methyl transferase in rat oesophagus and liver.

Several O6-alkylGua adducts have been shown to be removed from DNA during its repair by transfer of the alkyl group to a cysteine residue in a specific AAP, with the formation of S-alkylcysteine. As the reaction is stoichiometric and irreversible, the AAP content of the cell can be reduced or depleted. In vivo depletion by a high dose of nitrosamine can be used to test for the formation of a repairable alkylation adduct at the O6-position of guanine. In addition, if the carcinogenic potency of a nitroso compound for a particular organ is related to the persistence of the adduct in DNA, potency would depend not on the level of alkylation attained after treatment, but on whether this was sufficient to deplete the AAP content of the organ concerned and so to slow down repair, i.e. depletion of AAP is a more relevant estimate of potency than is the initial extent of DNA alkylation. Dose-response studies on target and non-target organs showed that depletion of AAP correlated with organotropy for those nitrosamines known to methylate DNA, i.e. with NDMA for liver, and with NMBzA for oesophagus. With NDEA, the results supported the suggestion that other adducts in addition to O6-alkylGua may be involved. NMPhA, an oesophageal specific carcinogen, did not deplete AAP in oesophagus, and induced AAP in liver. This result adds to the evidence that NMPhA does not alkylate DNA.

Alkylation↗
PubMed1997

Effect of erythromycin on gastric emptying in healthy individuals assessed by radio-opaque markers and plasma acetaminophen levels.

We simultaneously recorded gastric emptying of radio-opaque markers (ROMs) and monitored serial changes in plasma acetaminophen (AAP) levels to demonstrate the relationship between the ROM and the AAP methods, and we investigated the effect of a single intravenous dose of erythromycin (EM) on gastric emptying in healthy human subjects. After an overnight fast, subjects were randomized to receive either placebo or EM lactobionate (Abbott, North Chicago, IL, USA) 250 mg intravenously in a single dose, given immediately before a standard meal. Subjects ingested 1.5 g of AAP and ROMs with the test meal. A supine plain abdominal radiograph was taken 1, 2, 3, and 6 h after ingestion of the test meal. Peripheral blood samples were obtained 0, 0.5, 1, 1.5, 2, 3, and 6 h after ingestion of the test meal. EM significantly accelerated gastric emptying of ROMs. By 6 h, no markers remained in the stomach in any of the subjects in the placebo or EM groups. By 120 min, half of the ROMs had passed into the duodenum in 12.5% of subjects after placebo, whereas EM injection resulted in gastric emptying of half of the ROMs in all subjects. There was no difference in plasma AAP concentration between the placebo and EM groups. There were significant correlations between maximum plasma AAP concentration and gastric emptying of ROMs 120 min after ingestion (r = 0.546; P = 0.019), and between time of maximum plasma AAP concentration and gastric emptying of ROMs 120 min after ingestion (r = -0.568; P = 0.014). The time taken to reach the peak concentrations ranged from 30 to 90 min after ingestion, whereas most ROMs were emptied 120 min after ingestion. We conclude that the gastric emptying assessed by ROMs and by serial changes in plasma AAP level are good, non-invasive, clinically applicable tests, with a significant correlation between the two tests. A single intravenous dose of EM had a prokinetic effect on gastric emptying, assessed by ROMs, in healthy human subjects.

Acetaminophen↗
PubMed2000

A hepatotoxic dose of acetaminophen modulates expression of BCL-2, BCL-X(L), and BCL-X(S) during apoptotic and necrotic death of mouse liver cells in vivo.

The protein BCL-X(L) and protein product of proto-oncogene bcl-2 act as apoptosis antagonists, and BCL-X(S) serve as a dominant death promoter, including apoptosis following exposure to chemotherapeutic drugs. This investigation examined whether some aspects of the highly integrated process of acetaminophen (AAP)-induced hepatotoxicity involve down-regulation or upregulation of expression of BCL-2, BCL-X(L) and BCL-X(S) in mouse liver in vivo. Male ICR mice (CD-1; 35-45 g) were treated ip with a hepatotoxic dose of AAP (500 mg/kg) and sacrificed 0, 6, and 18 h later. Blood was collected upon sacrifice for determination of serum alanine aminotransferase (ALT) activity and the liver was sectioned for histopathological diagnosis of necrosis/apoptosis. Portions of liver tissues were also used for DNA extraction (for gel electrophoresis) and Western blot analysis. This study demonstrates that administration of a hepatotoxic dose of AAP to ICR mice results in severe liver injury (ALT leakage >200-fold at 6 h and >600-fold at 18 h) leading to massive cell death by apoptosis (diagnosed by nuclear ultrastructure, histopathology, and DNA ladder), in addition to necrosis coupled with spectacular changes in the BCL-X(L) expression (6 and 18 h after AAP administration). Western blot analysis of the liver proteins revealed that mouse liver expresses two proteins, BCL-X(L) and BCL-X(S), and does not express BCL-2. As the toxicity progressed, during 6 and 18 h post-AAP administration, the BCL-X(L) protein band shifted to a slower mobility band which might represent a phosphorylated form of BCL-X(L). Appearance of this higher molecular weight BCL-X(L) protein band correlated with massive apoptotic death of liver cells along with ladder-like DNA fragmentation. In the same time period, death inhibitory gene bcl-2 remained unexpressed, and the level of expression of BCL-X(S) remained unaltered. Whether the consistent level of expression of BCL-X(S) reflected inability of AAP to influence its expression remains unknown. Unaltered expression of BCL-X(S) in the near total absence of BCL-2 expression raises questions regarding the death promoting role of BCL-X(S) in vivo. The precise role of modified form of BCL-X(L) remains elusive. However, this study may have demonstrated for the first time drug-induced changes in the expression of anti-apoptotic gene BCL-X(L), and a positive link between AAP-induced apoptotic death and modification of BCL-X(L) protein in vivo.

Acetaminophen↗