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Biomedical subjects

M F Khan

Publications and source records attributed to M F Khan.

At least 55 records · Page 3Linked to original sources
PubMed1995

Erythrocyte-aniline interaction leads to their accumulation and iron deposition in rat spleen.

In order to understand the splenic toxicity of aniline in rats, early interaction of aniline with erythrocytes and its subsequent deposition and covalent binding to macromolecules in target (spleen) and nontarget (liver) organs have been studied. Male Sprague-Dawley (SD) rats were given 1 or 3 doses of 1 mmol/kg [14C]aniline hydrochloride (1 dose/d) by gavage and euthanized 24 h after the treatment. Among blood components, maximum radioactivity was found to be associated with red blood cells (RBCs). After 3 doses, there was 112, 79, and 67% increase in the radioactivity in the whole blood, RBCs, and hemolysate, respectively, in comparison to 1 dose. In comparison to RBCs, plasma had only 40 and 16% radioactivity after the administration of 1 and 3 doses, respectively. Spleen homogenate at 1 dose had one-third of the radioactivity in the TCA precipitate, which increased to 40% at 3 doses, while the total radioactivity increased 256% over 1 dose. Liver, which had almost double the radioactivity on a per gram tissue basis compared to the spleen at one dose, did not show any appreciable increase in the radioactivity at three doses. However, radioactivity in the TCA precipitate of liver homogenate increased by 92% after 3 doses. The iron content of the spleen in rats given 3 doses of [14C]aniline increased by 85% compared to the rats given just 1 dose. The iron content of liver did not show any change at three doses. These data thus demonstrate a dose-dependent binding and accumulation of radioactivity in erythrocytes and spleen. These interactions, along with parallel increases in the iron content of the spleen, could be critical in the splenic toxicity of anilines.

Aniline Compounds↗
PubMed1994

Age-related changes in beta-adrenergic neuroeffector systems in the human heart.

BACKGROUND: Aging decreases cardiac beta-adrenergic responsiveness in model systems and in humans in vivo. The purpose of this study was to comprehensively evaluate the age-related changes in the beta-receptor-G protein-adenylyl cyclase complex in nonfailing human hearts. METHODS AND RESULTS: Twenty-six nonfailing explanted human hearts aged 1 to 71 years were obtained from organ donors and subjected to pharmacological investigation of beta-adrenergic neuroeffector systems. When the population was subdivided into the 13 youngest and 13 oldest subjects, total beta-receptor density assessed by maximum [125I]ICYP binding (beta max) was reduced in older hearts by 37% in left ventricles and 31% in right ventricles (both P < .05), and the downregulation was confined to the beta 1 subtype (r = .78 left ventricle beta 1 density versus donor age). Older donor hearts exhibited a 3- to 4-fold rightward shift of ICYP-isoproterenol (ISO) competition curves and demonstrated 43% fewer receptors in a high-affinity agonist binding state (P < .05). Older hearts exhibited decreased adenylyl cyclase stimulation by ISO, by zinterol (beta 2-agonist), and by the G protein-sensitive probes forskolin, Gpp(NH)p, and NaF. In contrast, there was no change in response to manganese, a specific activator of the adenylyl cyclase catalytic subunit. Toxin-catalyzed ADP ribosylation in membranes prepared from older versus younger hearts revealed a 29% to 30% reduction (P < .05) with cholera toxin (Gs) but no difference with pertussis toxin (Gi). The systolic contractile response of isolated right ventricular trabeculae to ISO was decreased by 46%, with a 10-fold increase in ISO EC50 in older relative to younger donor hearts. CONCLUSIONS: There is a profound decrease in cardiac beta-adrenergic responsiveness with aging. This occurs by multiple mechanisms including downregulation and decreased agonist binding of beta 1-receptors, uncoupling of beta 2-receptors, and abnormal G protein-mediated signal transduction.

Adenylyl Cyclases↗
PubMed1993

Subchronic toxicity of aniline hydrochloride in rats.

Hematological, biochemical and histopathological responses of subchronic exposure to aniline hydrochloride (AH) have been investigated in rats. Male Sprague-Dawley rats were given 600 ppm of AH in drinking water while the control rats received tap water only. Five rats from each group were sacrificed at 30, 60, and 90 days of treatment. Organ-to-body weight ratio for spleen in the AH-treated rats was 56, 61, and 53% higher than controls at days 30, 60, and 90, respectively. Liver showed a biphasic pattern for this ratio, a decrease at 30 days and then an increase at 60 days. Among other organs, testes showed a significant decrease in this ratio at 60 days. Hematological analysis showed 65% increase in WBC counts at 30 days in the AH-treated rats, whereas, no changes were recorded at later time points. Erythrocyte counts in the AH-treated rats showed very significant decreases at all the time points, whereas, hemoglobin and hematocrit decreased at 30 and 90 days of treatment. Mean corpuscular volume and mean corpuscular hemoglobin increased in the AH-treated rats at 60 and 90 days of treatment. Methemoglobin content showed significant increases of 89, 59 and 45% at days 30, 60, and 90, respectively. Among serum immunoglobulins, IgA in the AH-treated groups showed 24 and 51% increases at days 60 and 90, respectively. Analysis of splenic lymphocyte subpopulation showed a decrease in the T-helper (CD4+/CD8-) sub-set at 90 days whereas, other subpopulations were not affected. Aniline hydroxylase activity in the liver microsomes of the AH-treated rats was significantly higher at 60 days of treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Aniline Compounds↗
PubMed1992

Stable superoxide dismutase (SOD)-mimetic ternary human serum albumin-Cu(II)(3,5-diisopropylsalicylate)2/Cu(II)2(3,5-diisopropylsalicylate)4 complexes in tissue distribution of the binary complex.

Copper(II)2(3,5-diisopropylsalicylate)4 [Cu(II)2(3,5-DIPS)4] has been found to have antiinflammatory, antiulcer, anticancer, anticonvulsant, antimutagenic, antidiabetic, analgesic, and radiation protection and recovery activities. It has also been found to reduce ischemia-reperfusion injury. Because of these activities it was of interest to understand how this compound is transported in the body to affected tissues. Evidence supporting the suggested formation of ternary human serum albumin (HSA)-Cu(II)(3,5-DIPS)2 or Cu(II)2(3,5-DIPS)4 complexes was obtained using ultraviolet spectrophotometry, dialysis, and atomic absorption spectrophotometry or atomic emission spectroscopy. Superoxide dismutase (SOD)-mimetic activity was also determined using the xanthine/xanthine oxidase/cytochrome c system. Ultraviolet spectra of aqueous solution mixtures of Cu(II)2(3,5-DIPS)4 in equilibrium with 2Cu(II)(3,5-DIPS)2 and HSA as well as aqueous solutions of solid Cu(II)2(3,5-DIPS)4 obtained by stirring the solid with an aqueous solution of HSA showed no obvious change in absorbance to indicate ternary complex formation. However, comparison of ultraviolet spectra taken before and after dialysis supports the suggested bonding of Cu(II)(3,5-DIPS)2 or Cu(II)2(3,5-DIPS)4 to HSA. Comparison of copper concentrations before and after dialysis also supports the suggested bonding of Cu(II)(3,5-DIPS)2 or Cu(II)2(3,5-DIPS)4 to HSA. Based upon these data it is plausible that Cu(II)(3,5-DIPS)2 or Cu(II)2(3,5-DIPS)4 form stable ternary complexes with HSA. These stable ternary complexes were also found to have SOD-mimetic activity.

Copper↗
PubMed1992

Effect of tetrakis-mu-3,5-diisopropylsalicylatodiaquodicopper(II) on the status of reduced glutathione in freshly isolated hepatocytes.

Effects of different concentrations of tetrakis-mu-3,5-diisopropylsalicylatodiaquodicopper(II) (Cu(II)2(3,5-DIPS)4(H2O2)2) on the reduced status of glutathione (GSH), the major nonprotein thiol in tissues, were investigated using freshly isolated hepatocytes. Cu(II)2(3,5-DIPS)4 below 100 microM did not have any significant effects on either the GSH content or viability of the hepatocytes, but at 150-250 microM it decreased both parameters after 1 h of incubation. The decrease in cellular GSH was not followed by an increase in the oxidized form of GSH (GSSG) in the cell suspension. The addition of deferoxamine with Cu(II)2(3,5-DIPS)4 to the hepatocyte suspension prevented depletion in GSH content and loss of cell viability by Cu(II)2(3,5-DIPS)4. Both GSH depletion and loss of cell viability were found to be Cu(II)2(3,5-DIPS)4 dose dependent. From these results, it appears that Cu(II)2(3,5-DIPS)4 penetrated the cell membrane and acted by decreasing the GSH level by forming a copper-glutathione complex.

Animals↗
PubMed1992

Toxic response of linoleic acid anilide in female rats.

The toxicity of linoleic acid anilide (LAA) and heated linoleic acid anilide (HLAA) was studied in female rats. Female Sprague-Dawley rats were given 250 mg/kg of LAA or HLAA in mineral oil, by gavage, on alternate days for two weeks. Control rats received an equal volume of mineral oil. The animals were sacrificed at day 1, 7 and 28 following the last dose. Organ-to-body weight ratio was increased for spleen in both LAA and HLAA treated rats at day 1. Lung, kidney and brain showed increases in this ratio at some time point, whereas, thymus in the HLAA group showed a decrease at day 28. Among blood parameters, red blood cells and hemoglobin content decreased in both LAA and HLAA treated groups at day 1 and in the LAA group at day 7. Serum IgA levels increased throughout the study in both treatment groups and were more pronounced in HLAA treated rats. Splenic T-helper lymphocyte numbers decreased in the HLAA group at day 1, whereas, other cell types were not affected. The changes observed in female rats are comparable to our previous findings in male rats and relatively minor in relation to sex differences. These results further support that hemopoietic system is an early target of fatty acid anilide toxicity.

Anilides↗
PubMed1992

Toxic response to repeated oral administration of 2-chloroethyl linoleate in rats.

In the present study, we investigated the toxic response to repeated oral administration of 2-chloroethyl linoleate (2-CEL) in male rats at 250 mg/kg body weight for 2 weeks on alternate days (total 7 doses). Control rats received an equal volume of mineral oil. The five animals from each group were sacrificed on days 1, 7 and 28 following the last dose. No significant changes were observed in body weight, as well as organ-to-body weight ratios due to 2-CEL treatment. The red blood cell counts increased significantly in 2-CEL treated animals at day 28 as compared to the controls. Elevated counts of platelets, monocytes and eosinophils and low counts of basophils and large unstained cells were also observed at some time points in 2-CEL treated rats. Significantly reduced activities of total serum lactate dehydrogenase (LDH), aspartate aminotransferase and alanine aminotransferase were found at most of the time points except for LDH at day 28. Adenosine triphosphatase activity was also significantly reduced in liver mitochondrial fraction at all time points. Histopathological studies showed consistent centrilobular lesions (incidence 4/4) in the liver consisting of hepatocyte vacuolar degeneration and focal necrosis at day 28. A few centrilobular lesions were also observed (incidence 2/4) at day 7, while no changes were observed at day 1. These results indicate that 2-CEL is a hepatotoxin, however, the observed decrease in serum enzyme levels in relation to hepatotoxicity of 2-CEL, needs to be elucidated.

Animals↗
PubMed1991

Copper(II) (3,5-diisopropylsalicylate)2 oxidizes thiols to symmetrical disulfides and oxidatively converts mixtures of 5-thio-2-nitrobenzoic acid and nonsymmetrical 5-thio-2-nitrobenzoic acid disulfides to symmetrical disulfides.

L-cysteine, D-penicillamine, and L-glutathione were oxidized to symmetrical disulfides in the presence of Cu(II)(3,5-DIPS)2 and air-oxygen at physiologic pH, 7.3. Air-oxygen caused the oxidation of thiol reduced copper, Cu(I), to Cu(II), as evidenced by expected spectrophotometric changes in these reaction mixtures. L-cysteine, D-penicillamine, and L-glutathione formed mixed disulfides and TNB with the addition of DTNB to solutions of these thiols. The observed order of reactivity for these thiols with DTNB was: L-cysteine greater than D-penicillamine greater than L-glutathione. Surprisingly, Cu(II)(3,5-DIPS)2 converted these mixed disulfides to their symmetrical disulfides and DTNB, and although the initial conversion rate was rapid, complete conversion required more than two hours. These observations suggest caution with regard to the spectrophotometric determination of thiols immediately after the addition of Ellman's reagent. These results also clarify an earlier report concerning the oxidation of thiols by Cu(II)(o-phenanthroline)2 and offer caution with regard to the determination of thiols using DTNB in the presence of copper complexes. Spectrophotometric data are provided in support of the suggestion that analysis of plasma or cellular samples for thiols be done in the absence of copper(II) complexes to avoid false negative results.

Cysteine↗
PubMed1991

Toxicity of oleic acid anilide in rats.

In the present investigation, we have studied the toxic potential of oleic acid anilide (OAA) and heated oleic acid anilide (HOAA) in relation to the toxic oil syndrome (TOS). Male Sprague-Dawley rats were given 250 mg/kg of OAA or HOAA in mineral oil by gavage, on alternate days for 2 weeks (total 7 doses). The control rats received an equal volume of mineral oil only. The animals were sacrificed at days 1, 7, and 28 following the last dose. Ratio of organ-to-body weight showed increases in spleen and kidney of HOAA and OAA treated rats, respectively, at day 1 while this ratio for liver in HOAA treated group showed a decrease at day 1. Among blood parameters, white blood cells increased in HOAA treated group at day 1 and in both OAA and HOAA groups at day 28. Mean corpuscular hemoglobin (MCH) and mean cell volume (MCV) also showed increases in the HOAA treated rats at days 7 and 28. Serum lactate dehydrogenase (LDH) decreased in both OAA and HOAA treated rats at day 1, while at day 7 the decrease was confined only to the HOAA group. Serum glutamic oxalacetic transaminase (GOT) and glutamic pyruvic transaminase (GPT) activities also decreased at most of the time points. Liver mitochondrial ATPase activity decreased in the HOAA group at day 7 and in the OAA group at day 28. Among serum immunoglobulins, IgA levels increased throughout the study but the changes were more pronounced in HOAA treated rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Anilides↗
PubMed1991

Bombesin-like peptides in alveolar macrophage: increased release in pulmonary inflammation and fibrosis.

Rat bronchoalveolar cells (99% alveolar macrophages (AM] were obtained by bronchoalveolar lavage and examined for their content of bombesin-like immunoreactivity (BLI) by radioimmunoassay (RIA), immunocytochemistry and high performance liquid chromatography (HPLC) analysis. Rat AM contained and released in their culture media significant levels of BLI, the major molecular form corresponding to gastrin-releasing peptide (GRP). Release of BLI by AM was not affected by in vitro activation of AM with lipopolysaccharide and muramyl dipeptide, but was enhanced following in vivo treatment with inflammatory agents. AM from animals with inflammation and fibrosis released higher levels of BLI than controls at 3 and 6 weeks after treatment. These changes were correlated with a significant increase in the proportion of low density mature AM as determined by Percoll density gradient fractionation. Together, our data indicate that increased release of BLI by AM may be related to AM maturation and support a role for bombesin-like peptides as modulator(s) of inflammatory reactions.

Animals↗
PubMed1991

Heated linoleic acid anilide: toxicity and relevance to toxic oil syndrome.

The present study was undertaken to investigate toxic potentials of linoleic acid anilide (LAA) and heated linoleic acid anilide (HLAA) and their possible role in the etiology of toxic oil syndrome (TOS). Male Sprague-Dawley rats were given 250 mg/kg of LAA or HLAA in mineral oil through gavage, on alternate days for 2 weeks (total 7 doses). Control rats received an equal volume of vehicle only. The animals were sacrificed at day 1, 7 and 28 following the last dose. Ratio of organ weight/body weight showed a significant increase in lung in LAA group at day 7 while spleen showed remarkable increases in both treatment groups at day 1 and 7. On the other hand, this ratio showed decreases in case of liver, brain and heart at some time points. Among blood parameters, red cell counts and hemoglobin content decreased at day 1 in both LAA and HLAA treated groups, while platelet counts showed an increase. Serum LDH, GOT and GPT activities significantly decreased at day 1 and 7 in both LAA and HLAA treated groups, however, these changes were more prominent in the HLAA treated group. Interestingly, at day 28, these serum enzyme levels recovered to control levels. Both LAA and HLAA treated groups showed a decrease in serum IgM levels at day 1, however, at day 7 only the LAA group showed a significant decrease. IgA levels significantly increased in both groups at all the time points studied and were more pronounced in the HLAA treated group. Similarly, IgG levels also showed increases in both the groups. In addition to serum immunoglobulin changes, alterations in the lymphocyte subpopulations were also observed. While T-cell population decreased, B-cell population remained unchanged. Among T-cell subsets, T-helper cells did not show any change while T-suppressor cells decreased significantly at day 1 in the LAA group and at day 1 and 7 in the HLAA group, but regained control levels at day 28. The biochemical and immunological alterations observed in this study as a result of LAA and HLAA exposure and more so by HLAA further support that the fatty acid anilides may play a role in the etiology of TOS.

Anilides↗
PubMed1991

Cellular and biochemical indices of bronchoalveolar lavage for detection of lung injury following insult by airborne toxicants.

Cellular and biochemical profiles of bronchoalveolar lavage (BAL) material after inhalation or intratracheal exposure to various airborne toxicants clearly reflect that BAL has the potential of being a useful tool for the rapid screening of lung injury. The cellular and biochemical responses not only predict inflammation, extent of tissue damage and toxic nature of the substances, but could also help in understanding the molecular mechanisms of pathogenicity. Depending upon the changes of BAL in animals acutely exposed to a pulmonary toxicant, future in-depth studies along with complete histopathological evaluations could be made. Also, the assessment of macromolecules of pharmacological importance in the lavage, especially the secretory products of alveolar macrophages and other lung cell types, could be very useful in predicting the toxic potential of various airborne substances and could also serve as important indicators of developing chronic lung diseases and, therefore, necessitate further studies.

Air Pollutants↗
PubMed1991

Synergistic vascular toxicity and fatty acid anilides in the toxic oil syndrome.

The underlying etiology of the toxic oil syndrome may be related to any of several toxic contaminants. The hypothesis is made that two or more toxic compounds may act synergistically to cause vascular damage in the toxic oil syndrome. To support this hypothesis, previous studies are reviewed concerning the remarkable synergistic toxic action of allylamine and beta-aminopropionitrile on the media of blood vessels. Although these toxins are not directly related to the toxic oil syndrome, this previous experimental work emphasizes the possibility that unexplored synergistic actions may be important. Furthermore, the hypothesis that contaminating fatty acid anilides in toxic oil undergo alterations during cooking is supported by high pressure liquid chromatographic analysis. The theoretic metabolism of fatty acid anilides is discussed. Recent data concerning the toxic actions of the anilides of oleic and linoleic acid are given. These data suggest that these anilides induce immunologic alterations that may be similar to those seen in the toxic oil syndrome. In addition, the heated anilides appear to have increased toxicity, supporting the concept that the use of toxic oil in cooking may increase its toxicity.

Allylamine↗
PubMed1991

Heated linoleic acid anilide reduces serum enzyme activities in rats.

In view of possible involvement of fatty acid anilides in toxic oil syndrome (TOS), the effects of linoleic acid anilide (LAA) and heated linoleic acid anilide (HLAA) on the activities of serum enzymes following their oral administration was studied in rats as a function of time. Serum glutamic oxalacetic transaminase (GOT) and glutamic pyruvic transaminase (GPT) activities decreased significantly in both LAA and HLAA treated rats at day 4. The decreases, however, were confined to only HLAA treated group at later stages with GOT activity showing significant decrease at day 8 and total lactate dehydrogenase (LDH) as well as GOT and GPT activities at day 12. Liver GOT activity at day 4 and LDH activity at day 8 decreased significantly in both LAA and HLAA treated rats. These findings indicate HLAA components may interact with plasma membranes and thereby, reducing the secretion of the enzymes into the serum.

Alanine Transaminase↗