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Biomedical subjects

R A Roth

Publications and source records attributed to R A Roth.

At least 91 records · Page 5Linked to original sources
PubMed1996

Platelet activating factor receptor blockade alone or in combination with leukotriene synthesis inhibition does not ameliorate alpha-naphthylisothiocyanate-induced hepatotoxicity.

Alpha-naphthylisothiocyanate (ANIT) is a cholangiolitic hepatotoxicant that causes periportal edema, hepatic parenchymal and biliary epithelial cell necrosis, and cholestasis in the rat. A hallmark of ANIT hepatotoxicity is periportal inflammation that includes neutrophil infiltration. Neutrophils are requisite for the expression of ANIT-induced liver injury; however, the mechanism(s) of neutrophil accumulation in the liver and the role of these cells in ANIT hepatotoxicity is incompletely understood. Platelet activating factor (PAF) is a proinflammatory agent that is both a chemoattractant for and an activator of neutrophils. Therefore, we evaluated the role of PAF in ANIT-induced liver injury. Rats were treated with the PAF receptor antagonist, WEB 2086 (WEB), to determine if it afforded protection from ANIT hepatotoxicity. In a separate study, a combination of WEB and the leukotriene synthesis inhibitor, Zileuton (ZIL), was used to address the possible interaction of PAF and leukotrienes in ANIT-induced liver injury. Treatment of rats with WEB, alone or in combination with Zileuton, did not attenuate ANIT-induced liver injury as assessed by increases in plasma alanine aminotransferase or gamma-glutamyl transferase activities. In addition, neither treatment ameliorated ANIT-induced cholestasis assessed as increased plasma bilirubin concentration. These results suggest that PAF, alone or in combination with products of 5-lipoxygenase, does not contribute to ANIT-induced liver injury.

1-Naphthylisothiocyanate↗
PubMed1996

Gadolinium chloride treatment attenuates hepatic platelet accumulation after lipopolysaccharide administration.

Intravenous administration of LPS to rats results in the accumulation of both neutrophils and platelets in the liver and the development of midzonal hepatocellular necrosis. The development of liver injury entails contributions from both cellular and soluble mediators, including neutrophils, platelets, Kupffer cells, tumor necrosis factor-alpha (TNF-alpha), and components of the coagulation system. Much remains unknown about the interactions among these mediators in the pathogenesis of liver injury in vivo. Accordingly, we conducted studies with gadolinium chloride (GdCl3), an agent that inhibits Kupffer cell phagocytosis, to evaluate the role of Kupffer cells in lipopolysaccharide (LPS)-mediated liver injury, elevation in plasma TNF-alpha activity, thrombocytopenia, hepatic platelet accumulation, and activation of the coagulation system. Female Sprague-Dawley rats were pretreated with GdCl3-6H2O (10 mg/kg, i.v.) or saline vehicle 24 h before the administration of LPS (4 mg/kg, i.v.) or saline vehicle. In a preliminary study, this GdCl3 treatment regimen decreased the clearance of colloidal carbon from blood, indicating inhibition of Kupffer cell phagocytosis. Pretreatment with GdCl3 attenuated LPS-induced liver injury, monitored as increased plasma alanine aminotransferase and isocitrate dehydrogenase activities and histologic analysis. Electron micrographs of livers from rats treated with LPS revealed platelets within the sinusoids as well as Kupffer cells with phagolysosomes containing material resembling platelets. Pretreatment with GdCl3 attenuated LPS-induced thrombocytopenia and hepatic platelet accumulation, as measured by radiolabeled platelets. Treatment with GdCl3 did not, however, alter the elevation in plasma TNF-alpha activity or the activation of the coagulation system, as evidenced by a decreased in plasma fibrinogen concentration. These results suggest that Kupffer cells contribute to LPS-induced hepatic platelet accumulation and raise the possibility that protection against LPS-induced hepatic injury by Kupffer cell inactivation may be due at least partly to decreased deposition of platelets within the liver.

Alanine Transaminase↗
PubMed1996

Role of the juxtamembrane tyrosine in insulin receptor-mediated tyrosine phosphorylation of p60 endogenous substrates.

Prior studies have demonstrated that a juxtamembrane tyrosine (tyrosine 972) in the insulin receptor is required for the receptor to elicit various biological responses and to stimulate the tyrosine phosphorylation of two endogenous substrates, the insulin receptor substrate-1 and the adaptor protein called Shc. In the present studies the role of this tyrosine was examined in the insulin-stimulated tyrosine phosphorylation of a group of 60-kDa endogenous proteins. These include a 60-kDa protein which, when phosphorylated, becomes associated with the GTPase activating protein of Ras, a distinct 60-kDa protein that associates with either the phosphatidylinositol 3-kinase or the tyrosine phosphatase Syp, as well as a 58/53-kDa protein that is tyrosine phosphorylated in response to insulin but has no known associated protein. In each case, a mutant insulin receptor in which tyrosine 972 has been changed to phenylalanine was found to be defective in its ability to phosphorylate these three endogenous substrates, although the mutant receptor exhibited the same level of insulin-stimulated autophosphorylation as the wild type receptor. These results further demonstrate the critical role that the juxtamembrane tyrosine 972 plays in downstream signaling by the insulin receptor.

Animals↗
PubMed1996

Lipopolysaccharide-induced hepatic injury is enhanced by polychlorinated biphenyls.

After intravenous administration of bacterial lipopolysaccharide (LPS) to rats, polymorphonuclear neutrophils (PMNs) rapidly accumulate in the liver, and midzonal hepatic necrosis is prominent by 6 hr. PMNs are required for the development of hepatic injury in rats. Certain polychlorinated biphenyls (PCBs) can activate PMNs, resulting in production of superoxide anion (O2-.) and release of cytolytic factors from granules. This raises the possibility that PCB exposure might enhance PMN-mediated tissue injury, such as LPS-induced hepatotoxicity. We treated female Sprague-Dawley rats with a minimally toxic dose of LPS in saline (2 mg/kg, intravenous) and 90 min later exposed them to Aroclor 1248 (50 mg/kg, intraperitoneal), a mixture of PCBs. The animals were killed 6 hr after LPS administration, and hepatic injury was assessed. Neither LPS nor Aroclor 1248 alone produced liver injury. Co-treatment with LPS and Aroclor 1248 resulted in pronounced liver injury as demonstrated from increased activities of alanine aminotransferase and isocitrate dehydrogenase in plasma. Histological evaluation indicated increased severity of hepatic necrosis in rats receiving both LPS and Aroclor 1248. Hepatic accumulation of PMNs, normally observed after LPS, was not altered by co-exposure to PCBs. Aroclor 1248 stimulated rat PMNs in vitro to produce O2-. and to degranulate. In addition, PMN-mediated cytotoxicity to isolated rat hepatocytes in culture was increased upon addition of Aroclor 1248. PCBs activate PMNs in vitro and increase PMN-dependent hepatocellular damage in vitro and after LPS treatment in vivo. PCBs may act in vivo as an additional inflammatory stimulus to activate PMNs to become cytotoxic, resulting in increased tissue injury.

Animals↗
PubMed1996

The thrombin inhibitor, hirudin, attenuates lipopolysaccharide-induced liver injury in the rat.

The administration of gram-negative bacterial lipopolysaccharide (LPS) to rats results in hepatic parenchymal cell injury within 6 hr. The coagulation system is critical to the pathogenesis, but previously reported results suggested that its critical role is independent of insoluble clot formation and that thrombin may be a key mediator of liver injury. To test the hypothesis that thrombin is involved in LPS-induced liver injury, animals were treated with the selective thrombin inhibitor, hirudin. The hirudin treatment regimen effectively inhibited thrombin, as evidenced by prolonged activated partial thromboplastin time and by maintenance of plasma fibrinogen concentrations in LPS-treated rats. Treatment with hirudin prevented LPS-induced liver injury, assessed by plasma alanine aminotransferase activity and histological evidence of hepatocellular necrosis. Previous studies have shown that LPS exposure results in the accumulation of neutrophils and platelets within the liver and that both of these cell types are critical for the development of LPS-induced liver injury. Hirudin attenuated in part the decrease in blood platelet concentration that accompanied LPS administration, but did not alter hepatic platelet or neutrophil accumulation. These results support the hypothesis that thrombin is required for hepatic injury from LPS exposure, but that it does not act by promoting the accumulation of platelets or neutrophils within the liver.

Animals↗
PubMed1995

A nonradioactive assay for the insulin receptor tyrosine kinase: use in monitoring receptor kinase activity after activation of overexpressed protein kinase C alpha and high glucose treatment.

In the present study we describe a nonradioactive assay for measuring the intrinsic tyrosine kinase activity of the insulin receptor. This assay utilizes as an exogenous substrate a biotinylated peptide based on the sequence of the endogenous substrate insulin receptor substrate-1 (IRS-1). To separate the tyrosine phosphorylated peptide from the nonphosphorylated peptide, immobilized recombinantly produced SH2 domain of the p85 subunit of the phosphatidylinositol 3-kinase is utilized to bind the tyrosine-phosphorylated peptide. The amount of bound peptide is then detected by the use of peroxidase-conjugated streptavidin and a colorimetric assay. This assay has been used to measure the tyrosine kinase activity of receptor which was immunocaptured from lysates of various cells overexpressing the human insulin receptor as well as the endogenous insulin receptors in the parental cells. In this in vitro assay, no decrease in tyrosine kinase activity was observed in receptors from cells with activated overexpressed protein kinase C alpha or after high glucose treatment although a decrease in in situ phosphorylation of IRS-1 was observed with the activation of protein kinase C alpha. These results indicate that this assay may be a useful new method for monitoring the enzymatic activity of the insulin receptor kinase as well as other tyrosine kinases.

Amino Acid Sequence↗
PubMed1995

Naphthylisothiocyanate disposition in bile and its relationship to liver glutathione and toxicity.

1-Naphthylisothiocyanate (ANIT), but not 2-naphthylisothiocyanate (BNIT), produces cholangiolitic hepatitis in rats after a single, oral administration. The mechanisms responsible for the disparate toxic outcomes for these closely related structural isomers are not fully understood. Recent reports suggest that ANIT-induced hepatotoxicity is dependent upon the formation and biliary excretion of a reversible glutathione-ANIT conjugate. To understand better the relationship between hepatic glutathione, secretion into bile and hepatotoxicity, the bile concentrations and hepatotoxicities of ANIT and BNIT were examined in rats with and without pretreatment with buthionine sulfoximine (BSO). ANIT (100 mg/kg, p.o.) caused a 3-fold elevation of plasma alanine aminotransferase activity (ALT), a 6-fold elevation of total plasma bilirubin, and a > 90% reduction in bile flow 24 hr after administration. BNIT, at this same dose and route of administration, did not alter significantly these markers of liver injury. Accumulation of ANIT and BNIT in bile occurred with the same temporal characteristics; however, BNIT accumulated to markedly larger concentrations (292 +/- 83 and 235 +/- 100 microM BNIT and 78 +/- 19 and 29 +/- 13 microM ANIT at 1 and 4 hr, respectively). The accumulation of ANIT and BNIT in bile was coincident with a > 2-fold elevation of reduced glutathione in bile. Pretreatment of rats with BSO decreased hepatic glutathione concentration and reduced the concentration of naphthylisothiocyanates in bile by 85%. Associated with this reduction was an attenuation of ANIT hepatotoxicity. Altogether, these findings indicate that both ANIT and BNIT accumulate in bile in a glutathione-dependent manner, yet they yield different hepatotoxic outcomes. Therefore, the disparity in hepatotoxicities observed with these isomers is not related to a difference in ability to enter bile. Other differences, such as in metabolism, chemical reactivity, conjugate stability and/or cytotoxic potential to bile duct epithelial cells may be more important determinants of hepatotoxicity.

1-Naphthylisothiocyanate↗
PubMed1995

Grb-IR: a SH2-domain-containing protein that binds to the insulin receptor and inhibits its function.

To identify potential signaling molecules involved in mediating insulin-induced biological responses, a yeast two-hybrid screen was performed with the cytoplasmic domain of the human insulin receptor (IR) as bait to trap high-affinity interacting proteins encoded by human liver or HeLa cDNA libraries. A SH2-domain-containing protein was identified that binds with high affinity in vitro to the autophosphorylated IR. The mRNA for this protein was found by Northern blot analyses to be highest in skeletal muscle and was also detected in fat by PCR. To study the role of this protein in insulin signaling, a full-length cDNA encoding this protein (called Grb-IR) was isolated and stably expressed in Chinese hamster ovary cells overexpressing the human IR. Insulin treatment of these cells resulted in the in situ formation of a complex of the IR and the 60-kDa Grb-IR. Although almost 75% of the Grb-IR protein was bound to the IR, it was only weakly tyrosine-phosphorylated. The formation of this complex appeared to inhibit the insulin-induced increase in tyrosine phosphorylation of two endogenous substrates, a 60-kDa GTPase-activating-protein-associated protein and, to a lesser extent, IR substrate 1. The subsequent association of this latter protein with phosphatidylinositol 3-kinase also appeared to be inhibited. These findings raise the possibility that Grb-IR is a SH2-domain-containing protein that directly complexes with the IR and serves to inhibit signaling or redirect the IR signaling pathway.

Adipose Tissue↗
PubMed1995

Activation of protein kinase C alpha inhibits signaling by members of the insulin receptor family.

Stimulation of the activity of protein kinase C by pretreatment of cells with phorbol esters was tested for its ability to inhibit signaling by four members of the insulin receptor family, including the human insulin and insulin-like growth factor-I receptors, the human insulin receptor-related receptor, and the Drosophila insulin receptor. Activation of overexpressed protein kinase C alpha resulted in a subsequent inhibition of the ligand-stimulated increase in antiphosphotyrosine-precipitable phosphatidylinositol 3-kinase mediated by the kinase domains of all four receptors. This inhibition varied from 97% for the insulin receptor-related receptor to 65% for the Drosophila insulin receptor. In addition, the activation of protein kinase C alpha inhibited the in situ ligand-stimulated increase in tyrosine phosphorylation of the GTPase-activating protein-associated p60 protein as well as Shc mediated by these receptors. The mechanism for this inhibition was further studied in the case of the insulin-like growth factor-I receptor. Although the in situ phosphorylation of insulin-receptor substrate-1 and p60 by this receptor was inhibited by prior stimulation of protein kinase C alpha, the in vitro tyrosine phosphorylation of these two substrates by this receptor was not decreased by prior stimulation of the protein kinase C alpha in the cells that served as a source of the substrates. Finally, the insulin-like growth factor-I-stimulated increase in cell proliferation was found to be inhibited by prior activation of protein kinase C alpha.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1995

Insulin stimulates the kinase activity of RAC-PK, a pleckstrin homology domain containing ser/thr kinase.

In the present study, insulin is shown to rapidly stimulate by 8- to 12-fold the enzymatic activity of RAC-PK alpha, a pleckstrin homology domain containing ser/thr kinase. In contrast, activation of protein kinase C by phorbol esters had almost no effect on the enzymatic activity of RAC-PK alpha. Insulin activation was accompanied by a shift in molecular weight of the RAC-PK alpha protein, and the activated kinase was deactivated by treatment with a phosphatase, indicating that insulin activated the enzyme by stimulating its phosphorylation. This insulin-induced shift in RAC-PK was also observed in primary rat epididymal adipocytes, as well as in a muscle cell line called C2C12 cells. The insulin-stimulated increase in RAC-PK alpha activity was inhibited by wortmannin (an inhibitor of phosphatidylinositol 3-kinase) in a dose-dependent manner with a half-maximal inhibition of 10 nM, but not by 20 ng/ml of rapamycin. Activation of RAC-PK alpha activity was also observed in a variant RAC lacking the pleckstrin homology domain. These results indicate that RAC-PK alpha activity can be regulated by the insulin receptor. RAC-PK alpha may therefore play a general role in intracellular signaling mediated by receptor tyrosine kinases.

Animals↗
PubMed1995

Leukotrienes and alpha-naphthylisothiocyanate-induced liver injury.

alpha-naphthylisothiocyanate (ANIT) administration to rats results in periportal hepatic inflammation and injury. Glutathione (GSH) appears to be necessary for the liver injury to occur. The leukotrienes (LTs) are metabolites of arachidonic acid and potent mediators of inflammation that have been implicated in certain liver injury models. Inasmuch as GSH is a cofactor for the synthesis of cysteinyl-LTs and since inflammation is a prominent component of ANIT injury, we hypothesized that LTs are involved in producing the hepatic insult that results from ANIT administration. To test this hypothesis, rats were treated with one of several inhibitors of LT biosynthesis, A63162, Zileuton or MK-886. Each of these agents prevented the formation of LTB4 in Ca++ ionophore-stimulated whole blood from rats treated with the inhibitors. A63162 attenuated the hepatic parenchymal injury caused by ANIT and resulted in a modest decrease in ANIT-induced cholestasis. In contrast, neither Zileuton nor MK-886 attenuated liver injury. AT-125 (Acivicin) inhibits gamma-glutamyl transferase (GGT), the enzyme that catalyzes the formation of LTD4 from LTC4. AT-125 pretreatment did not prevent ANIT-induced hepatic parenchymal insult. It did, however, ameliorate the cholestasis caused by ANIT. In conclusion, the partial protection afforded by A63162 and AT-125 likely results from effects unrelated to the formation of LTs, since Zileuton and MK-886 inhibited LT synthesis without affording protection. The lack of protection by Zileuton and MK-886 in the face of LT synthesis inhibition suggests that LTs are not necessary for the expression of injury after ANIT administration.

1-Naphthylisothiocyanate↗
PubMed1995

Comparison of the signaling abilities of the Drosophila and human insulin receptors in mammalian cells.

Chimeric receptors encoding either the whole or a portion of the cytoplasmic domain of the drosophila insulin receptor (IR) with the extracellular domain of the human IR were expressed either transiently in COS cells or stably in Chinese hamster ovary cells and compared with the wild-type human IR. All three receptors bound insulin equally and exhibited an insulin-activated tyrosine kinase activity. The ability of the drosophila cytoplasmic domain to mediate the tyrosine phosphorylation of insulin receptor substrate 1, stimulate cell proliferation, and activate MAP kinase was found to be indistinguishable from that of the human IR. The chimeric drosophila receptors did not bind more phosphatidylinositol 3-kinase than the human IR, despite containing a C-terminal extension with potential tyrosine phosphorylation sites in the motif recognized by the SH2 domain of this enzyme. Thus, the essential signal-transducing abilities of the IR appear to have been conserved from invertebrates to mammals, despite the considerable differences in the sequences of these receptors.

Animals↗
PubMed1995

Characterization of the endogenous insulin receptor-related receptor in neuroblastomas.

A gene encoding a putative third member of the insulin receptor family (called the insulin receptor-related receptor or IRR) was isolated in 1989. However, the naturally occurring protein product encoded by this gene has yet to be described. In the present studies, we have generated four monoclonal antibodies to a recombinantly expressed chimera, which contains the extracellular domain of human IRR. These antibodies were found to specifically recognize the chimeric IRR (and not the insulin or insulin-like growth factor I receptors), and two of the antibodies were capable of acting as partial agonists in the cells expressing the chimeric IRR. These antibodies have therefore been utilized to study the expression and properties of the native receptor. In contrast to the two other members of this receptor family, the endogenous IRR protein had only a very limited expression, being detected only in neuroblastomas. In primary neuroblastomas, the levels of the receptor were highest in samples from stage A tumors (those which are generally more highly differentiated and have higher levels of the nerve growth factor receptor). The endogenous IRR could also be detected in a neuroblastoma cell line (called IMR-5 cells). In these cells, IRR could be shown to be partly present as a hybrid with the insulin and insulin-like growth factor-I receptors but not with the receptor for nerve growth factor. The intrinsic tyrosine kinase activity of this endogenous IRR was activated by the agonist monoclonal antibody to IRR but not by nerve growth factor, insulin-like growth factor I, or insulin. Finally, this monoclonal antibody was found to stimulate mitogen-activated protein kinase activity in these cells. In summary, these studies demonstrate for the first time that the IRR protein is normally expressed, that its levels are highest in neuronal tissues, and that it can form hybrid receptors with the two other members of this receptor family but not with the more distantly related nerve growth factor receptor.

Amino Acid Sequence↗
PubMed1995

1-naphthylisothiocyanate-induced elevation of biliary glutathione.

1-Naphthylisothiocyanate (ANIT) has been used for many years to study cholangiolitic hepatotoxicity in laboratory animals. Hallmarks of ANIT hepatotoxicity include portal edema and inflammation with bile duct epithelial and hepatic parenchymal cell necrosis. In rats, ANIT hepatotoxicity is dependent upon hepatic glutathione. Studies in vitro have demonstrated that ANIT combines reversibly with glutathione and suggest that intracellular formation and secretion of this glutathione-ANIT conjugate from hepatic parenchymal cells may be responsible for the efflux of glutathione observed upon exposure to ANIT. In vivo, glutathione conjugates produced within hepatic parenchymal cells are typically transported into bile for elimination. Therefore, large concentrations of ANIT in bile may result from hepatic parenchymal cell secretion of a reversible glutathione-ANIT conjugate. To investigate this hypothesis, bile and plasma concentrations of ANIT were determined in rats 1, 4, 8, 12 and 24 hr after administration (100 mg/kg, p.o.). Liver and bile glutathione concentrations were also evaluated. Plasma ANIT concentrations ranged between 2 and 5 microM at 1, 4, 8 and 12 hr and were 0.9 microM at 24 hr after administration. ANIT concentrations in bile at 1, 4, 8 and 12 hr were 60, 28, 21 and 22 microM, respectively. Thus, ANIT was concentrated in bile. Hepatic glutathione was not affected by ANIT during the first 12 hr after administration; however, a moderate elevation occurred by 24 hr. In contrast, a marked elevation in bile glutathione concentration (two times control) occurred 1, 4 and 8 hr after ANIT administration. Thus, the early accumulation of ANIT in bile was coincident with an elevation in bile glutathione. These findings support the hypothesis that glutathione functions to concentrate ANIT in bile. The large concentration of this toxicant in bile may be injurious to bile epithelium, a primary cellular target in ANIT hepatotoxicity.

1-Naphthylisothiocyanate↗
PubMed1995

Toxicity of mitomycin C toward cultured pulmonary artery endothelium.

Mitomycin C (MMC) is a bifunctional alkylating agent used in cancer chemotherapy. MMC therapy occasionally results in pulmonary vascular injury, including alterations in endothelial cells. Reactive metabolites of MMC can cross-link DNA, and its cytotoxicity has been attributed in part to this capacity, but effects in vascular cells have not been explored extensively. Accordingly, the direct effects of MMC on cultured porcine pulmonary artery endothelial cells (PECs) were examined. A single administration of MMC (0-10 microM) to PEC monolayers resulted in concentration-dependent cytolytic injury that was delayed in onset and progressive in nature. Cells treated at subconfluent densities were inhibited in their ability to proliferate. MMC treatment resulted in DNA cross-linking at concentrations (0.01-1 microM) that inhibited cell proliferation but caused only limited overt cytotoxicity, supporting an association between DNA cross-linking and impairment of cell division. This pattern of PEC injury is reminiscent of that seen after treatment with another pneumotoxic, bifunctional alkylating agent, monocrotaline pyrrole. The similarity of the endothelial cell response to different bifunctional alkylating agents suggests that DNA cross-linking may inhibit cell proliferation and thereby limit the repair capacity of endothelial monolayers. This might contribute to the progressive pulmonary vascular injury that occurs after administration of certain DNA cross-linking agents in vivo.

Alkylation↗
PubMed1995

Chemical-induced vasculature injury. Summary of the symposium presented at the 32nd annual meeting of the Society of Toxicology, New Orleans, Louisiana, March 1993.

The cross-sectional structure of the vasculature is comparatively simple, comprising three layers--the intima, adjacent to the lumen, the media, and the adventitia. Notwithstanding this simplicity, the vessels are host to a variety of reactions to injury. Two cell types, endothelial cells of the intima and smooth muscle cells of the media, are principal targets of damage and repair. The endothelial cells of the intimal layer of the vessel wall present a macromolecular barrier and are important in maintaining vessel integrity. When the integrity is compromised by physical or chemical injury, endothelial cells play a key role in the repair processes. The use of single-cell wound models allows the mechanisms of damage and subsequent repair to be studied in depth. Repair processes can be observed using time-lapse photography and differences between cytoskeleton changes during repair and reendothelialization of small and large wounds can be discriminated. In rats treated with the plant toxin monocrotaline, pulmonary vascular injury occurs which manifests as thrombosis and remodeling with consequent progressive pulmonary hypertension. In vivo and in vitro studies of the mechanism of monocrotaline toxicity suggest that the endothelial cells are an important target. In vitro studies show monocrotaline to be directly cytotoxic; in cells that survive, there are functional changes to the endothelial cells, resulting in a decreased repair capability which may lead to the complex, progressive lung lesions that develop. The other target cells of the vasculature are the smooth muscle cells of the media. Ingestion of primary amines allylamine and beta-aminopropionitrile (beta-APN) results in chronic vasculotoxicity to the aorta and medium-sized arteries. For allylamine, subtle changes in smooth muscle result in medial hypertrophy and subintimal proliferation. The changes are slow to occur, taking weeks or months of repeated treatment. For beta-APN, which is the active ingredient of the toxic sweet pea Lathyrus odoratous, vascular toxicity is manifested by fatal rupture of aortic aneurysms. When these agents are administered concomitantly, a synergistic acute smooth muscle necrosis occurs in large elastic arteries and degenerative changes are seen in muscular arteries. A change in the target for toxicity of allylamine toward the vasculature may be responsible for this synergistic toxic insult. Medial smooth muscle necrosis is also noteworthy after administration of certain pharmaceutical agents of diverse structure and pharmacological activity. These agents induce arteriopathies in dogs and rats, although at different sites. In dogs, the coronary arteries are susceptible, whereas in rats the mesenteric arteries are the principal sites of injury.(ABSTRACT TRUNCATED AT 400 WORDS)

Amines↗
PubMed1995

Vitamin A or zymosan pretreatment attenuates alpha-naphthylisothiocyanate-induced liver injury.

alpha-Naphthylisothiocyanate (ANIT) is a cholangiolitic hepatotoxicant that causes periportal hepatic injury in the rat that is neutrophil- and platelet-dependent. Since macrophages have recently been implicated as participants in some chemically induced hepatotoxicities, we evaluated the role of these cells in ANIT-induced hepatic injury. Rats were treated with gadolinium chloride (GdCl3), an agent which decreases hepatic macrophage numbers and activity, zymosan, an agent which increases hepatic macrophage numbers, or vitamin A, which increases hepatic macrophage activity. GdCl3 did not ameliorate ANIT-induced hepatotoxicity, as demonstrated by a lack of attenuation of any of the markers of hepatic insult evaluated. In contrast, pretreatment with either zymosan or vitamin A decreased ANIT hepatotoxicity. Zymosan administration reduced blood neutrophil numbers and influx of neutrophils into the peritoneum after intraperitoneal glycogen administration but did not affect hepatic neutrophil accumulation in ANIT-treated rats. To determine if macrophages were important in the protection by vitamin A, rats were cotreated with GdCl3 and vitamin A. GdCl3 did not alter the protection from ANIT hepatotoxicity afforded by vitamin A. Vitamin A treatment decreased ANIT and glutathione concentrations in bile at 1 and 4 hr after ANIT administration but had a minimal effect on plasma ANIT concentration. In summary, pretreatment of rats with zymosan or vitamin A but not GdCl3 attenuated ANIT-induced liver injury. The protection afforded by zymosan may derive from its effects on neutrophils or platelets. The protection by vitamin A appears to result from its effect on the transport of ANIT into bile. The results suggest that hepatic macrophages are not required for the manifestation of ANIT hepatotoxicity.

1-Naphthylisothiocyanate↗