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Z Zhao

Publications and source records attributed to Z Zhao.

At least 253 records · Page 14Linked to original sources
PubMed1996

Characterization and genomic mapping of genes and pseudogenes of a new human protein tyrosine phosphatase.

Previously described protein tyrosine phosphatases (PTPs) are classified into three types according to their sequence homology and structural features. Here we describe the characterization of genes and pseudogenes of a member of a fourth type of PTP, designated protein tyrosine phosphatase 4A (PTP4A). The 167-amino-acid human PTP4A bears the signature active site of all PTPs, but does not show any other sequence homology to any of the previously described PTPs. Two cDNAs encoding PTP4A that differed in their noncoding regions were isolated. Another cDNA that has a high level of sequence identity with these two cDNAs and a deletion in the coding region was also isolated. Northern analysis using a probe from a common 3'-untranslated region of the cDNAs recognized mRNAs of about 2 and 4 kb. Both species of mRNA were seen in all human adult and fetal tissues tested. Fluorescence in situ hybridization mapping of the corresponding yeast artificial chromosome clones and sequence-tagged site analysis suggested that one of the PTP4A coding genes is located at 1p35 and the other is on chromosome 11. A processed pseudogene for PTP4A was found in the BRCA1 region of 17q21 and shares 96% sequence identity to one of the PTP4A coding cDNAs. Our studies also suggest the existence of another processed pseudogene on chromosome 11.

Adult↗
PubMed1996

Brain metabolism patterns are sensitive to attentional effort associated with a tone recognition task.

Using positron emission tomography with the tracer 18-fluoro-D-deoxyglucose, we assessed regional cerebral glucose utilization patterns (rCMRglu) associated with three performance levels in a forced choice, tone recognition task. Four normal subjects responded with one hand when they heard a high-frequency tone (1500 Hz), and with the other hand when they recognized a low-frequency tone (750 Hz). The EASY (EAS) condition accuracy average was 96%, the INTERMEDIATE level accuracy averaged 89%, and the DIFFICULT (DIF) recognition task accuracy average was 77%. Statistical parametric mapping (SPM94) analysis revealed that the DIF minus EAS contrast is associated with a marked metabolic elevation in the right middle and inferior temporal gyri and the gyrus fusiformis. The EAS minus DIF contrast revealed greater rCMRglu in the right medial geniculate body. Enhanced activity in right temporal lobe structures may reflect a role in auditory memory and "image" visualization. The medial geniculate enhancement may reflect tone frequency assessment.

Adult↗
PubMed1996

Rabbit liver phosphofructokinase: rapid purification and phosphorylation site identification.

Liver phosphofructokinase can be selectively precipitated by the addition of protamine sulfate to a heat-treated crude extract and redissolved, giving nearly full recovery of catalytic activity in combination with a 67-fold increase in specific activity. We have incorporated protamine sulfate precipitation into a five step purification procedure that can be completed in one day--giving 47% recovery of electrophoretically homogeneous liver phosphofructokinase having a specific activity of 50 units/mg. The radio-labeled fragment isolated from a CNBr digest of liver phosphofructokinase that has undergone in vitro phosphorylation catalyzed by the cAMP-dependent protein kinase has the sequence AEYVSGELEHVTRRSLS.

Adenosine Triphosphate↗
PubMed1996

Positive effect of overexpressed protein-tyrosine phosphatase PTP1C on mitogen-activated signaling in 293 cells.

PTP1C, an SH2 domain-containing protein-tyrosine phosphatase, is predominantly expressed in hematopoietic cells, in which it negatively regulates cellular signaling. However, this enzyme is also expressed in many non-hematopoietic cells. We demonstrate here that in non-hematopoietic 293 cells, overexpression of a catalytically inactive mutant of PTP1C strongly suppressed the stimulatory effects of the epidermal growth factor or serum on cell proliferation, early gene transcription, and DNA synthesis. Similarly, the phosphorylation of the mitogen-activated protein kinase and mitogen-activated protein kinase kinase activity was markedly inhibited by overexpression of mutant PTP1C. The inhibitory effect of mutant PTP1C was overcome by cotransfection with wild-type PTP1C, but not with the structurally related PTP2C. Furthermore, expression of the mutant phosphatase resulted in hyperphosphorylation on tyrosine of a 95-kDa protein that was co-immunoprecipitated with the mutant, but not with the wild-type protein. These results suggest that, unlike in hematopoietic cells, PTP1C in 293 cells plays a positive role in epidermal growth factor- or serum-activated mitogenesis. Thus, PTP1C participates in multiple signaling pathways, where the enzyme, depending on its target molecules, may function as either a positive or negative mediator.

Cell Division↗
PubMed1996

Farnesol is not the nonsterol regulator mediating degradation of HMG-CoA reductase in rat liver.

A recent report, in which cultured tumor cells were used, identified farnesol as the nonsterol mevalonate-derived metabolite required for the accelerated degradation of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (C. C. Correll, L. Ng, and P. A. Edwards, 1994, J. Biol. Chem. 269, 17390-17393). We examined this proposed linkage in animals by measuring hepatic farnesol levels and rates of HMG-CoA reductase degradation under conditions previously shown to alter the stability of the reductase. In normal rats, the hepatic farnesol level, quantified by high-pressure liquid chromatography, was 0.10 +/- 0.08 microgram/g and the half-life of HMG-CoA reductase was 2.5 h. Administration of mevalonolactone at 1 g/kg body wt to provide all nonsterol metabolites in addition to cholesterol increased farnesol levels 6-fold without significantly affecting the half-life of the reductase. Treatment of rats with zaragozic acid A, an inhibitor of squalene synthase, raised hepatic farnesol levels 10-fold and decreased the half-life of HMG-CoA reductase to 0.25 h. However, feeding lovastatin to rats did not lower hepatic farnesol levels despite a marked stabilization of HMB-CoA reductase protein. Moreover, intubation of rats with 500 mg/kg body wt of farnesol failed to decrease the half-life of HMG-CoA reductase protein, alter the levels of enzyme activity, or change of the levels of immunoreactive protein despite an increase of 1000-fold in hepatic farnesol levels. These observations indicate that farnesol per se does not induce accelerated degradation of HMG-CoA reductase in rat liver.

Animals↗
PubMed1996

CD22 associates with protein tyrosine phosphatase 1C, Syk, and phospholipase C-gamma(1) upon B cell activation.

Cross-linking B cell antigen receptor (BCR) elicits early signal transduction events, including activation of protein tyrosine kinases, phosphorylation of receptor components, activation of phospholipase C-gamma (PLC-gamma), and increases in intracellular free Ca2+. In this article, we report that cross-linking the BCR led to a rapid translocation of cytosolic protein tyrosine phosphatase (PTP) 1C to the particulate fraction, where it became associated with a 140-150-kD tyrosyl-phosphorylated protein. Western blotting analysis identified this 140-150-kD protein to be CD22. The association of PTP-1C with CD22 was mediated by the NH2-terminal Src homology 2 (SH2) domain of PTP-1C. Complexes of either CD22/PTP-1C/Syk/PLC-gamma(1) could be isolated from B cells stimulated by BCR engagement or a mixture of hydrogen peroxidase and sodium orthovanadate, respectively. The binding of PLC-gamma(1) and Syk to tyrosyl-phosphorylated CD22 was mediated by the NH2-terminal SH2 domain of PLC-gamma(1) and the COOH-terminal SH2 domain of Syk, respectively. These observations suggest that tyrosyl-phosphorylated CD22 may downmodulate the activity of this complex by dephosphorylation of CD22, Syk, and/or PLC-gamma(1). Transient expression of CD22 and a null mutant of PTP-1C (PTP-1CM) in COS cells resulted in an increase in tyrosyl phosphorylation of CD22 and its interaction with PTP-1CM. By contrast, CD22 was not tyrosyl phosphorylated or associated with PTP-1CM in the presence of wild-type PTP-1C. These results suggest that tyrosyl-phosphorylated CD22 may be a substrate for PTP-1C regulates tyrosyl phosphorylation of CD22.

Antigens, CD↗
PubMed1996

Thiophosphate derivatives as inhibitors of tyrosine phosphatases.

Thiophosphorylated proteins or peptides are poor substrates of protein phosphatases. As a competitive inhibitor of a protein tyrosine phosphatase, a tyrosine-thiophosphorylated nonapeptide ENDYINASL displays a KI value of 0.25 microM, in comparison with the Km value of 3.1 microM exerted by the enzyme toward the phosphorylated form of the peptide. Furthermore, adenosine 5'-O-3-thiotriphosphate is also an effective competitive inhibitor of the enzyme with a KI value of 1.4 microM. In contrast, ATP and 5'-adenylimidodiphosphate are much less effective, indicating that the thiophosphate group plays a major role in the inhibition process. Further supporting this is the fact that sodium thiophosphate is a more effective inhibitor than inorganic phosphate (IC50 = 0.47 mM versus 15 mM). The inhibition by thiophosphate compounds is specific for PTPs. The data suggest the application of thiophosphate derivatives as specific inhibitors of PTPs.

Amino Acid Sequence↗
PubMed1996

Inhibitors of cholesterol biosynthesis increase hepatic low-density lipoprotein receptor protein degradation.

Inhibitors of cholesterol biosynthesis are believed to lower serum cholesterol levels by enhancing the removal of serum low-density lipoprotein (LDL) by increasing hepatic LDL receptor function. Thus, the effects of several different inhibitors of cholesterol biosynthesis were examined for their effects on the expression of the hepatic LDL receptor in rats. We found that administration of inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase such as lovastatin, pravastatin, fluvastatin, and rivastatin resulted in increased hepatic LDL receptor mRNA levels. Surprisingly, these agents failed to increase levels of immunoreactive LDL receptor protein in rat liver even when the dose and length of treatment were increased. Treatment of rats with zaragozic acid A, an inhibitor of squalene synthase, caused even greater increases in hepatic LDL receptor mRNA levels, but did not increase levels of immunoreactive protein. Further investigation revealed that the rate of degradation of the hepatic LDL receptor was increased in rats given inhibitors of cholesterol biosynthesis. The greatest increase in the rate of degradation was seen in animals treated with zaragozic acid A which caused the largest increase in hepatic LDL receptor mRNA levels. In contrast, hepatic LDL receptor protein was stabilized in cholesterol-fed rats. It appears that increased potential for LDL receptor protein synthesis, reflected in increased mRNA levels, is offset by a corresponding increase in the rate of receptor protein degradation resulting in constant steady-state levels of hepatic LDL receptor protein. These findings are suggestive of increased cycling of the hepatic LDL receptor. This postulated mechanism can provide for enhanced hepatic uptake of lipoproteins without increasing steady-state levels of LDL receptor protein.

Animals↗
PubMed1996

The interface of capillary electrophoresis with high performance Fourier transform ion cyclotron resonance mass spectrometry for biomolecule characterization.

The interfacing of capillary electrophoresis (CE) with Fourier transform ion cyclotron resonance-mass spectrometry (FTICR-MS) and the factors which dictate obtainable performance (i.e., sensitivity, mass resolution, scan rate and duty cycle) are described. We demonstrate the current status of the technique with examples of capillary zone electrophoresis (CZE) and capillary isotachophoresis (CITP) with FTICR analyses of proteins and oligonucleotides, and describe current limitations on sensitivity and scan speed. The first on-line interfacing of capillary isoelectric focusing (CIEF) with FTICR is also demonstrated and shown to be effective for separating minor components of protein mixtures for on-line mass spectral analysis. Finally, the potential for greatly improved performance based upon recent advances in FTICR instrumentation and methods is briefly described.

Animals↗
PubMed1996

Increasing hepatic cholesterol 7alpha-hydroxylase reduces plasma cholesterol concentrations in normocholesterolemic and hypercholesterolemic rabbits.

The effect of bile acid depletion and replacement with glycodeoxycholic acid on plasma cholesterol concentrations, hepatic low-density lipoprotein (LDL) receptor binding and messenger RNA (mRNA) levels, and hepatic activities and mRNA levels for 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and cholesterol 7alpha-hydroxylase was investigated in 19 New Zealand white (NZW) and 15 Watanabe heritable hyperlipidemic (WHHL) rabbits. Bile acid depletion was produced by external bile drainage for 5 days, which maximized cholic acid synthesis. Replacement was achieved by infusing glycodeoxycholic acid intraduodenally for 24 hours so that the hepatic bile acid flux reached prefistula levels. Plasma and liver cholesterol concentrations were 13 times and 50% greater, respectively, hepatic LDL receptor-mediated binding was 26% less, and cholesterol 7alpha-hydroxylase activity and mRNA levels were 62% and 86% less in WHHL than NZW rabbits. After bile drainage, plasma cholesterol concentrations decreased 29% in NZW rabbits and 40% in WHHL rabbits and were associated with a 2.1-fold increase in hepatic LDL receptor-mediated binding in the NZW rabbits, but there was no change in the WHHL rabbits. Cholesterol 7alpha-hydroxylase activity and mRNA levels increased three and four times in NZW and WHHL rabbits, respectively, although liver cholesterol levels remained unchanged. Replacement with exogenous glycodeoxycholic acid increased plasma cholesterol concentrations 1.7 times in NZW rabbits and decreased enhanced cholesterol 7alpha-hydroxylase activity 54%, mRNA levels 86%, cholic acid synthesis 38%, and hepatic LDL receptor-mediated binding 57% in NZW rabbits. Bile acid depletion stimulated cholic acid synthesis by up-regulating cholesterol 7alpha-hydroxylase to use cholesterol and reduce plasma concentrations substantially in both NZW and WHHL rabbits, although LDL receptors did not function in WHHL rabbits. Glycodeoxycholic acid replacement inhibited elevated cholesterol 7alpha-hydroxylase, cholic acid synthesis, and hepatic LDL receptor binding to reestablish baseline plasma cholesterol levels in NZW rabbits. Hypercholesterolemia in WHHL rabbits was related to the combination of dysfunctional LDL receptors and inhibited cholesterol 7alpha-hydroxylase. Plasma cholesterol concentrations were reduced significantly when cholesterol 7alpha-hydroxylase was stimulated even in the absence of LDL receptor function.

Animals↗
PubMed1996

A new transgenic mouse model for the study of cell cycle control in megakaryocytes.

During the development of the megakaryocytic lineage, the megakaryoblasts give rise to megakaryocytes which undergo repeated S phases in the absence of cytokinesis (endomitosis). The cellular oncogene myc plays a central role in the proliferation and differentiation of several cell types. In a previous study, we generated transgenic mice carrying c-myc fused to the estrogen receptor under the control of the platelet factor four (PF4) megakaryocyte-specific promoter. The bone marrow of female transgenic mice, but not of male mice, displayed increased megakaryopoiesis. Here we report that beta-estradiol-induced activation of c-myc in cultured bone marrow cells derived from male or female transgenic mice resulted in prolonged survival of the cells in vitro. Addition of a cocktail of hemopoietic growth factors to beta-estradiol-treated cells, including interleukin 6 (IL-6), IL-3 and stem cell factor further improved the survival time in culture and increased the percentage of large mature cells, but did not result in immortalization. The majority of these PF4-expressing cells, however, did not reach the differentiation stage at which acetylcholinesterase is expressed and did not appear as large megakaryocytes. We conclude that cultured megakaryocytes overexpressing myc are induced to proliferate, but have a limited potential to fully differentiate. Under these conditions, cyclin D3 was downregulated while the level of cyclin A was slightly upregulated.

Acetylcholinesterase↗
PubMed1996

Experimental study on the early efficacy of excimer laser with adjunctive balloon angioplasty in dog's femoral artery.

The effect of domestically-manufactured excimer laser with adjunctive balloon angioplasty in achieving revascularization and reduction of residual stenosis was assessed. 20 femoral arteries with thrombosis and occlusion from 12 dogs were subject to angiography. At first excimer laser angioplasty was done followed by balloon angioplasty. The diameter and residual stenosis of revascularized vessel were measured. The result showed that 17 out of 20 vessels (85%) were revascularized. The diameter of revascularized vessel by excimer laser were 1.22 +/- 0.14 mm, while residual stenoses were 54% +/- 5%. After adjunctive balloon angioplasty the diameter and residual stenoses were 2.04 +/- 0.16 mm and 20% +/- 7% respectively (P < 0.05 and P < 0.01). Complication in form of vasoperforation occurred in 3/20 vessels (15%). It is concluded that China- manufactured excimer laser angioplasty is effective when used for revascularization. While the reduction of narrowing and residual stenoses was enhanced after adjunction of balloon angioplasty. This method can be employed in treating peripheral occlusive disease effectively and safely.

Angioplasty, Balloon, Laser-Assisted↗
PubMed1996

Pharmacokinetics and antitumor effects of mitoxantrone after intratumoral or intraarterial hepatic administration in rabbits.

The intratumoral (i.t.) delivery of anticancer drugs aims at controlling tumor growth and thereby provides palliative treatment for liver neoplasms. Mitoxantrone is a good candidate for local or regional administration because (1) its metabolism is mainly hepatic, (2) it has a steep dose-response curve for multiple solid tumors, and (3) its fixation in tissues is sustained without vesicant effects after extravasation. We compared the tolerance, pharmacokinetics, and antitumor effects of mitoxantrone on hepatic VX2 tumors in rabbits treated with i.t. intraarterial hepatic (i.a.h.) or i.v. mitoxantrone, i.t. ethanol; or i.t. 0.9% NaCl and in control animals. Tumor growth rates (TGRs) were evaluated at 9 days after treatment. Myelosuppression was the limiting toxicity of i.v. mitoxantrone at 1.5 mg/kg (maximal tolerated dose, MTD), but neither i.t. nor i.a.h. administration led to hematologic toxicity at the same dose. The mitoxantrone retained in tumors after i.t. administration was seen as blue-stained areas of complete necrosis according to histologic analysis. Pharmacokinetic parameters showed a significantly decreased systemic exposure to the drug after both regional treatments, although the i.a.h. route appeared to have an edge over the i.t. route. TGRs were significantly reduced after i.t. mitoxantrone (81 +/- 62%), i.a.h. mitoxantrone (337 +/- 110%), and i.t. ethanol treatments (287 +/- 117%) as compared with control values (886 +/- 223%; p < 0.01). Treatment with i.v. mitoxantrone (816 +/- 132%) had no antitumor effect, nor did NaCl injections (868 +/- 116%). Mitoxantrone given i.t. induced the highest antitumor effects, resulting in a 3.5-fold reduction in TGRs as compared with i.a.h. mitoxantrone and i.t. ethanol treatments (p < 0.02). Treatment with i.t. mitoxantrone provided efficient antitumor therapy without producing major side effects. This method should be considered as palliative treatment for nonresectable liver tumors and other localized malignancies.

Animals↗
PubMed1996

Molecular dissection of a cosmid from a gene-rich region in 17q21 and characterization of a candidate gene for alpha-N-acetylglucosaminidase with two cDNA isoforms.

A cosmid mapped to human Chromosome (Chr) 17q21, c140c10, was found to contain a CpG island. We completed the sequence analysis of c140c10 because of two considerations: the cosmid contained an STS from the 17-beta-hydroxysteroid dehydrogenase gene (17-HSD), which was believed to be a neighbor of the breast cancer susceptibility gene, BRCA1; CpG islands are usually associated downstream and/or upstream of human genes. Computer-based exon trapping of the cosmid sequence revealed putative additional exons. With two of those exons used as a probe to screen human placental cDNA libraries, two cDNA isoforms for a novel gene, designated as ufHSD, were isolated. The amino acid sequence of the open reading frames of the cDNA showed no significant homology to any protein in the data base. However, it is possible that our cDNAs are from the gene for alpha-acetylglucosaminidase, which has recently been localized to the same region. Northern analyses show that the major isoform is expressed in all tissues tested, with the highest expression in blood leukocytes and lowest in brain. Finally, our study has shown that the 46.7-kb cosmid c140c10 encompasses loci for five genes and pseudo-genes: PsiPTP4A, ufHSD, 17-HSDI, 17-HSDII, and 22A1.

Acetylglucosaminidase↗
PubMed1996

A study of the three-dimensional organization of the human diaphragmatic lymphatic lacunae and lymphatic drainage units.

The peritoneal stomata, lymphatic drainage units and subperitoneal terminal lymphatics, called lymphatic lacunae, form a specialized drainage system in the diaphragm, by which absorption of fluid in bulk, particles and cells is carried out in the peritoneal cavity. The aim of this study is to elucidate the three-dimensional organization and function of the subperitoneal lymphatic lacunae and lymphatic drainage units by using lymphatic casts in the scanning electron microscope (SEM), ODO (OsO4-DMSO-OsO4) freeze fracture, conventional SEM and the transmission electron microscope (TEM). The subperitoneal lymphatic lacuna is unique for its large size and its multiple morphology and can be recognized by its broad, flattened enlargement and the blind-ends of lymphatic vessels, from which extend numerous main lymphatic vessels and side branches. These lymphatic vessels communicate with each other and form a rich lymphatic plexus under the diaphragmatic peritoneum. Two layers of lymphatic networks, i.e. the subperitoneal plexus and the deeper plexus are found in the muscular portion. Only one layer is present in the tendinous portion of the human diaphragm. The lymphatic plexus is denser in the tendinous portion than that in the muscular portion. The lymphatic lacunae occur exclusively in the muscular portion of the human diaphragm. The lumina of lymphatic lacunae are separated from the peritoneal cavity by a barrier consisting of cuboidal mesothelial cells, endothelial cells of the lymphatic lacunae and intervening connective tissue forming a lymphatic drainage unit. All these three components of the lymphatic drainage unit abut upon each other, but are not linked by specialized junctions. The cuboidal mesothelial cells frequently extend valve-like cytoplasmic processes that bridge the subperitoneal channel and make give it a tortuous course. The fibrous layer of the connective tissue is arranged in fiber bundles and gives a three-dimensional network forming the floor of the peritoneal stomata and the roof of the lymphatic lacunae. Via the fibrous network, the cuboidal mesothelial cells and the endothelial cells of the lacunae come into close contact with each other and form short subperitoneal channels which connect the peritoneal cavity with the subperitoneal lymphatic lacunae. The lymphatic drainage units may regulate the material absorption of the peritoneal stomata from the peritoneal cavity. It is suggested that the peritoneal stomata together with the subperitoneal channels, lymphatic drainage units and lymphatic lacunae comprise an important diaphragmatic lymphatic drainage system which plays an important role in the absorption of materials from the peritoneal cavity.

Diaphragm↗
PubMed1996

Controlled delivery of antigens and adjuvants in vaccine development.

Advances in the understanding of the pathogenesis of infectious diseases and cancer immunology have inspired many new approaches to vaccine development. Many subunit antigens and peptides that are effective for vaccination have been discovered. These subunit antigens in tum stimulate synthesis of effective adjuvants to enhance their immunogenicity. Controlled-release technology offers the potential of further improving the efficacy of conventional vaccine formulations by optimizing the temporal and spatial presentation of the-antigens and adjuvants to the immune system. The combination of sustained release and depot effect may also reduce the amount of antigens or adjuvants needed and eliminate the booster shots that are necessary for the success of many vaccinations. This review examines the contribution controlled release technology can make in various areas of vaccination, with an emphasis on tumor vaccines.

Adjuvants, Immunologic↗
PubMed1996

Bioactivation of 6,7-dimethyl-2,4-di-1-pyrrolidinyl-7H-pyrrolo[2,3-d]pyrimidine (U-89843) to reactive intermediates that bind covalently to macromolecules and produce genotoxicity.

U-89843 is a novel pyrrolo[2,3-d]pyrimidine antioxidant with prophylactic activity in animal models of lung inflammation. During preclinical safety evaluation, U-89843 was found to give a positive response in the in vitro unscheduled DNA synthesis (UDS) assay, an assay which measures DNA repair following chemically-induced DNA damage in metabolically competent rat hepatocytes. Incubation of [14C]U-89843 with liver microsomes resulted in covalent binding of radioactive material to macromolecules by a process that was NADPH-dependent. U-89843 has been shown to undergo C-6 methylhydroxylation to give U-97924, in rat both in vivo and in vitro, in a reaction catalyzed by cytochrome P450 2C11. Synthetical U-97924 is chemically reactive and undergoes dimerization in aqueous solution. The dimerization of U-97924 was significantly inhibited by addition of nucleophiles such as methanol, glutathione, and N-acetylcysteine. Characterization of the corresponding methanol, glutathione, and N-acetylcysteine adducts of U-97924 supported the hypothesis of a reaction pathway involving reactive iminium species formed via dehydration of U-97924. The metabolism-dependent irreversible covalent binding of radioactive material to liver microsomal protein and DNA also is dramatically reduced in the presence of reduced glutathione (GSH). A trifluoromethyl analog of U-89843 was prepared in an effort to block the corresponding metabolic hydroxylation pathway. This new compound (U-107634) was found to be negative in the in vitro UDS assay, and its metabolic susceptibility toward hydroxylation at the C-6 methyl group was eliminated. These observations suggest that the positive in vitro UDS results of U-89843 are mediated by the bioactivation of U-89843, leading to reactive electrophilic intermediates derived from the (hydroxymethyl)pyrrole metabolite U-97924.

Animals↗