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Biomedical subjects

R C Gupta

Publications and source records attributed to R C Gupta.

At least 199 records · Page 11Linked to original sources
PubMed1989

Activity dependent characteristics of fast and slow muscle: biochemical and histochemical considerations.

The effects of denervation and hindlimb suspension induced disuse on concentrations of ATP, phosphocreatine (PC), and fiber type profile were investigated in slow twitch soleus and fast twitch extensor digitorum longus (EDL) muscles. The results show that the soleus and EDL muscles differ in their dependency on loadbearing as a stimulus for maintaining normal energy metabolism and the biochemical and morphological characteristics of muscle fibers. As determined by R-P methodology, suspension reduced ATP and PC concentrations of the soleus to 26% and 56%, respectively, while, in EDL only, PC is reduced to 71% of control with no change in ATP. Both muscles, however, show identical losses in ATP and PC following denervation. The energy charge, an indicator of Pi availability in muscle was reduced significantly in both denervated muscle to 82% and 85% in soleus and EDL, respectively. No significant reduction of the energy charge was seen in the muscles from suspended rats. Thus, in parallel with the indirect regulation through muscle loadbearing, the nerve can effectively modulate the levels of high-energy phosphates more directly by some regulatory mechanisms independent of muscle type. Denervation and suspension disuse increased the proportion of type 2 fibers in the soleus with a concomitant decrease in type 1 fibers and a relative rise in the number of very small diameter fibers. The EDL showed only variation in fiber size.

Adenosine Diphosphate↗
PubMed1989

High performance liquid chromatographic (HPLC) determination of centchroman in human serum and application to single-dose pharmacokinetics.

A simple and sensitive (2 ng/ml) HPLC method with fluorescence detection has been developed to measure serum concentrations of centchroman, a new nonsteroidal antifertility agent. The method was sufficiently sensitive to follow the drug over 21 days in human volunteers. Pharmacokinetic parameters of centchroman were determined after a single oral dose of 60 mg (2 x 30-mg tablets) in two healthy female volunteers. Centchroman is slowly eliminated from serum, showing a biexponential disappearance curve from serum. The terminal half-life of centchroman in the two volunteers was 168 and 175 hr, respectively.

Adult↗
PubMed1989

Concerted role of carboxylesterases in the potentiation of carbofuran toxicity by iso-OMPA pretreatment.

Pretreatment of rats with the nonspecific esterase inhibitor iso-OMPA (1 mg/kg sc) 1 h prior to carbofuran (2,3-dihydro-2,2-dimethyl-7-benzofuranyl N-methylcarbamate, 0.5 mg/kg sc) administration potentiated carbofuran toxicity by more than threefold. Neither iso-OMPA nor carbofuran in the given doses produced any gross toxic signs. Rats receiving combined treatment, however, showed severe hypercholinergic signs (salivation, tremors, muscle fasciculations, and convulsions) within 5-10 min following carbofuran administration, and the severity was comparatively greater than that observed with an acute dose of carbofuran (1.5 mg/kg sc). Rats pretreated with iso-OMPA (0.5 mg/kg) died within 10-15 min following the acute dose of carbofuran (1.5 mg/kg). Each drug when given alone (1.0 mg/kg iso-OMPA, 0.5 mg/kg carbofuran) caused a significant (p less than .01) inhibition of carboxylesterase (CarbE) activity in brain structures (cortex, stem, striatum, and hippocampus), skeletal muscle (hemidiaphragm), liver, and plasma, whereas acetylcholinesterase (AChE) activity remained significantly (p greater than .01) unchanged. The maximal CarbE inactivation in plasma (less than 14% remaining activity) following either drug indicated a tremendous nonspecific binding to non-AChE serine-containing enzymes. iso-OMPA pretreatment markedly potentiated carbofuran's anticholinesterase activity both in neuronal and in nonneuronal tissues. It can be concluded that iso-OMPA pretreatment potentiates carbofuran toxicity either by preventing nonspecific binding of carbofuran to CarbE and/or possibly by inhibiting its detoxification.

Animals↗
PubMed1989

Prevention and antagonism of acute carbofuran intoxication by memantine and atropine.

Male Sprague-Dawley rats administered with a sublethal acute dose of carbofuran (1.5 mg/kg, sc) developed the observable toxic signs of anticholinesterase nature within 5-7 min. The toxic signs with increasing propensity to maximal severity including tremors, generalized muscle fasciculations, and convulsions were evident during 15 min to 1 h and lasted for 2 h. Thereafter, signs were seen up to 3 h with reduced intensity. By the end of 3.5 h toxic signs were completely subsided. Maximal acetylcholinesterase (AChE) inactivation occurred at 1 h in discrete brain regions (cortex, stem, striatum, and hippocampus) and hemidiaphragm muscle when most severe signs of toxicity were also evident. A single sc dose of memantine HCl (MEM, 18 mg/kg) and atropine sulfate (ATS, 16 mg/kg) 60 and 15 min, respectively, prior to carbofuran administration completely prevented the expected gross toxic signs and significantly (p less than .01) attenuated the carbofuran-induced inhibition of AChE activity. When given therapeutically, this combined treatment completely reversed the clinical evidence of carbofuran toxicity within 15 min and also markedly reduced AChE inactivation. Memantine or atropine when given alone was less effective compared to their combined administration. The results of this study suggested that, in addition to cholinolytic effects of atropine, memantine may prevent and antagonize the acute toxicity of carbofuran by (a) protection of AChE activity and its rapid reactivation from inhibition and (b) rapid elimination of carbofuran.

Acetylcholinesterase↗
PubMed1989

Formation and removal of DNA adducts in target and nontarget tissues of rats administered multiple doses of 2-acetylaminophenanthrene.

2-Acetylaminophenanthrene (2-AAP) is carcinogenic for the mammary gland, small intestine and ear duct in rats, but is not hepatocarcinogenic. In order to understand the tissue specificity of tumor induction, the formation and removal of DNA adducts in target and nontarget tissues have been compared in rats administered 2-AAP. Male and female Sprague--Dawley rats were treated i.p. with up to four weekly doses of 5 mg 2-AAP per kg body weight. 32P-Post-labeling analysis of the DNA from all tissues showed two predominant adducts (greater than 85-95% of the total binding) and at least four minor adducts. By comparing the results obtained from reacting N-hydroxy-2-aminophenanthrene with DNA at pH 5, the major adducts were identified as N-(deoxyadenosine-8-yl)-2-aminophenanthrene and 1-(deoxyguanosin-N2-yl)-2-aminophenanthrene. Two minor adducts, N-(deoxyadenosine-8-yl)-2-aminophenanthrene and 1-(deoxyadenosin-N6-yl)-2-aminophenanthrene, were also formed in the in vitro reactions. The distribution of adducts, extent of binding and adduct persistence were similar between target and nontarget tissues, which indicates that the tissue specificity of 2-AAP for tumor induction is due to factors in addition to adduct formation.

Animals↗
PubMed1989

Sensitivity of rat and mouse peripheral blood lymphocytes to BaP adduction and SCE formation.

Both mice and rats were injected i.p. with doses of benzo[a]pyrene (BaP) ranging from 10 to 100 mg/kg to compare species sensitivity to and the relationship between sister chromatid exchange (SCE) induction and DNA adduct formation. Twenty-four hours after injection, blood was removed by cardiac puncture and the peripheral blood lymphocytes (PBLs) were analyzed for both DNA adduct formation by 32P-postlabeling and SCE induction following lymphocyte culture. BaP induced similar, but not identical, SCE dose-response curves for each species. After BaP administration, the major DNA adduct, N2-[10 beta-(7 beta,8 alpha,9 alpha-trihydroxy-7,8,9,10- tetrahydrobenzo[a]pyrene)yl]deoxyguanosine (BPDEI-dGuo), was approximately 10-fold more prevalent in the PBLs of the mouse than those of the rat. Thus, for equivalent amounts of BPDEI-dGuo, a greater number of SCEs are induced in the rat than the mouse.

Animals↗
PubMed1989

Natural environment surpasses polluted environment in inducing DNA damage in fish.

Measurement of specific DNA adduct concentrations in target tissues of organisms may provide a key biologic end-point of exposure to environmental carcinogens. Using a general and highly sensitive assay with 32-P-postlabeling, we found that natural populations of freshwater fish species chub, barbel, bream and carp, as well as a marine fish mugil, revealed the presence of four to nine qualitatively similar adducts irrespective of whether they were caught from unpolluted or polluted waters. No statistically significant differences were observed between the adduct levels of fish from the unpolluted waters and those of fish from the polluted waters. A dominant feature of the fish DNA adducts was a species specificity. The finding that a vast majority of DNA modifications in fish are caused by natural factors rather than man-made chemicals offers a basis for a more realistic view in assessing the genotoxic risks in any aquatic environment.

Animals↗
PubMed1989

Acute pulmonary edema associated with the use of oral ritodrine for premature labor.

We describe a patient who developed acute pulmonary edema while taking oral ritodrine for the treatment of premature labor and recovered after its discontinuation. The mechanism of development of pulmonary edema associated with beta-sympathomimetic agents is still not fully understood. Patients taking oral ritodrine should be observed for cardiopulmonary signs and symptoms.

Acute Disease↗
PubMed1988

Susceptibility of glucose-6-phosphate dehydrogenase deficient red cells to primaquine enantiomers and two putative metabolites--I. Effect on reduced glutathione, methemoglobin content and release of hemoglobin.

The effects of the primaquine (PQ) enantiomers, (+)PQ and (-)PQ, and two putative metabolites [5-hydroxyprimaquine (5HPQ) and 6-desmethyl-5-hydroxyprimaquine (6D5HPQ)] on methemoglobin (Met Hb) and glutathione content and release of hemoglobin into plasma from glucose-6-phosphate dehydrogenase (G-6-PD) deficient red cells were studied in vitro. The results show that a 1.5 mM concentration of (-)PQ produced a significantly greater increase in Met Hb content and decrease in reduced glutathione (GSH) level than did (+)PQ. However, the release of plasma hemoglobin was greater with (+)PQ than with (-)PQ. The hydroxy derivatives of primaquine, 5HPQ and 6D5HPQ, were significantly more active than PQ. Their individual effects differed; whereas 5HPQ produced significantly greater reduction in GSH compared to 6D5HPQ, the effect of 6D5HPQ on Met Hb content and release of plasma hemoglobin was greater than that of 5HPQ. The qualitative effects of these compounds on normal, heterozygous and hemizygous G-6-PD deficient red cells were similar, but quantitatively the effects were greatest on hemizygous G-6-PD deficient cells and intermediate on heterozygous cells.

Erythrocytes↗
PubMed1988

Hepatic DNA adduct formation in rats treated with benzo[f]quinoline.

The formation of hepatic DNA adducts in male Sprague-Dawley rats following i.p. administration of benzo[f]quinoline (BfQ) was examined using a 32P-post-labeling assay. BfQ exhibited a low binding (11-27 amol adducts/microgram DNA) to liver DNA. Two BfQ-nucleoside adducts (one major and one minor) were detected. The BfQ-DNA adducts formed in vivo were chromatographically distinct from the adducts formed by the reaction of calf thymus DNA in vitro with BfQ-5,6-oxide, syn-7 beta,8 alpha-dihydroxy-9 beta,10 beta-epoxy-7,8,9,10-tetrahydroBfQ, anti-9 alpha,10 beta-dihydroxy-7 alpha,8 alpha-epoxy-7,8,9,10-tetrahydroBfQ, or anti-7 beta,8 alpha-dihydroxy-9 alpha,10 alpha-epoxy-7,8,9,10-tetrahydroBfQ-N- oxide. These results suggest that the bay-region diol epoxide of BfQ, unlike the bay-region diol epoxide derivatives of polynuclear aromatic hydrocarbons, is not involved in the covalent binding of BfQ to DNA.

Animals↗
PubMed1988

Analysis of DNA adducts in putative premalignant hepatic nodules and nontarget tissues of rats during 2-acetylaminofluorene carcinogenesis.

Exposure of rats to a standard four-cycle feeding regimen of 0.06% 2-acetylaminofluorene (AAF) results in the formation of putatively premalignant hepatic nodules, but the types and magnitude of DNA adducts formed in these nodules has not been previously examined. By using a sensitive 32P-adduct assay (R. C. Gupta, Cancer Res., 45: 5656-5662, 1985), we analyzed the DNA adduct lesions in individual hepatic nodules at various times during and after exposure to AAF. Kidney, spleen, and testis were included as nontarget tissues. No qualitative difference was observed in the DNA adducts found in hepatic nodules and nontarget tissues; however, quantitative differences occurred. At least one unknown and two known (dG-C8-AF and dG-N2-AAF) DNA adducts were detected, with dG-C8-AF being predominantly (96-98%) formed, in all tissues examined. At the end of the first three weeks of AAF feeding, the concentration of the deacetylated adduct dG-C8-AF in liver (223 fmol/micrograms DNA) was found to be about 2, 6, and 5 times higher than in kidney, spleen, and testis, respectively. The concentration of the N2-acetylated adduct in liver (4.5 fmol/micrograms DNA) was 4-fold higher than in kidney and strikingly higher (51- and 42-fold, respectively) than in spleen and testis. At the end of the fourth feeding cycle, total DNA adducts measured in the hepatic nodules ranged from 30-100 fmol/micrograms DNA, while the "surrounding liver," kidney, spleen, and testis showed 235, 218, 62, and 28 fmol adducts/micrograms DNA, respectively. Sixty days following the cessation of AAF, the binding in both the persistent nodules and liver had decreased to 7% of their respective levels measured at the end of the fourth cycle, while adducts in kidney, spleen, and testis were 32%, 18% and 19%. After 88 days, the binding levels in the nontarget tissues declined further, but no additional adduct removal occurred in the nodules. Our data indicate that (a) although the metabolic apparatus for activation of AAF is diminished in the hepatic nodules, a significant level of adduct formation occurs in the cells of this putative, premalignant lesion, and (b) unlike in the nontarget tissues, repair processes in the premalignant nodules may not be operative several weeks after the cessation of AAF exposure.

2-Acetylaminofluorene↗
PubMed1988

32P-adduct assay: short- and long-term persistence of 2-acetylaminofluorene-DNA adducts and other applications of the assay.

32P-Postlabeling techniques have been developed to detect and measure adducts formed by covalent binding of carcinogens of known or unknown origin with DNA (and RNA). The assay is applicable to various classes of chemical carcinogens and permits detection of many adducts at attomole (10(-18) mol) level using microgram amounts of DNA. Here, we demonstrate the application of the assay for the analysis of short- and long-term persistence of 2-acetylaminofluorene-DNA adducts in rat liver in vivo and also outline examples illustrating the applicability of the procedure to different experimental problems.

2-Acetylaminofluorene↗
PubMed1988

Interaction of fibronectin with DNA/anti-DNA complexes from systemic lupus erythematosus: role of activated complement Cl in modulation of the interactions.

Fibronectin (Fn) is an integral constituent of the endothelial cell surface and the basement membrane. The mechanism for binding DNA/anti-DNA complexes to Fn was examined in a solid-phase assay. In physiological buffer, a low-affinity binding of DNA was observed with Fn and optimal binding was seen at pH 6.5 and in the absence of Ca2+. Further, the interaction of DNA to Fn was inhibited when DNA was complexed to anti-DNA antibody. However, complement Clq mediated the binding of complexes to Fn at pH 7.4 and it was proportional to the extent of the dissociation of Cl. Cl inactivator (Cl-In) appeared to play a modulating role; whereas at low concentrations (Cl:Cl-In::4: less than 1) it enhanced the binding of complexes to Fn, higher concentrations inhibited the binding. Further, sera from patients with active systemic lupus erythematosus reacted with Fn, which was shown to be dependent on the presence of Clq and was minimally affected by DNase treatment of sera, indicating a relatively minor role of DNA in the direct binding of DNA to Fn. These findings support "circulating immune complex" hypothesis in the pathogenesis of lupus glomerular immune complex deposition disease.

Antibodies, Antinuclear↗
PubMed1988

Prevention of diisopropylphosphorofluoridate (DFP)-induced skeletal muscle fiber lesions in rat.

The objective of the present investigation was to assess the comparative efficacy of prophylactic treatment with d-tubocurarine (d-TC) (0.075 mg/kg), atropine sulfate (16 mg/kg), and atropine methylnitrate (16 mg/kg), employed singly or in combination against the diisopropylphosphorofluoridate (DFP)-induced myopathy in rat. DFP (1.5 mg/kg, s.c.) produced signs of cholinergic toxicity with predominantly peripheral involvement manifest as severe muscle fasciculations beginning within 5-7 min and persisting in excess of 4-6 h. Maximal muscle fiber necrosis was observed within 24 h. Rats were protected against the apparent behavioural and morphological changes as well as electrophysiological signs of neuromuscular toxicity by all pretreatment agents. Combined pretreatment with d-TC (0.075 mg/kg, s.c.) and atropine methylnitrate (16 mg/kg, s.c.) was found to be most effective in attenuating DFP-induced muscle fiber necrosis as evidenced by complete absence of lesions and the prevention of DFP-induced hyperactivity in nerve and muscle. Significant protection was afforded by all pretreatment agents when given alone. It is suggested that the pretreatment agents act presynaptically by preventing drug-induced backfiring and muscle fasciculations possibly by reducing the release of acetylcholine (ACh). The protective drugs in the concentrations used had no significant effect on the normal characteristics of conduction and transmission.

Action Potentials↗
PubMed1988

Use of human peripheral blood lymphocytes to measure DNA binding capacity of chemical carcinogens.

Although animal models have been used successfully to study metabolic activation and binding of carcinogens to DNA, only limited studies have been done in human systems. To circumvent the problems associated with the inaccessibility of human tissues and a lack of sensitive methods to detect DNA damage, we have investigated the capability of human peripheral blood lymphocytes in vitro to metabolize carcinogens to their DNA binding species by a 32P-labeled adduct assay. Freshly isolated lymphocytes were exposed at 37 degrees C for 18 hr to 4-aminobiphenyl, 2-aminofluorene, 2-anthramine, 2-acetylaminophenanthrene, benzidine, 1-nitropyrene, 1,2-benzanthracene, triphenylene, 7,12-dimethylbenz[a]anthracene, or benzo[a]pyrene at 30 microM each, compounds that are shown or suspected to be carcinogenic in experimental animals. Anthracene, pyrene, and perylene were included as noncarcinogenic controls. Our data indicate that all test carcinogens formed readily measurable levels of DNA adducts. Analysis of exposed DNAs by 32P-labeling after digestion and adduct enrichment showed exclusively or predominantly one major adduct for all test carcinogens, except for 2-anthramine, triphenylene, and 7,12-dimethylbenz[a]anthracene, which showed two or three adducts, in the range of 8-1500 amol/micrograms of DNA. No DNA binding was detected for the noncarcinogens. From 12 lymphocyte specimens studied thus far, significant interindividual variations were observed for 2-aminofluorene (62-fold), 7,12-dimethylbenz[a]anthracene (10-fold), benzidine (19-fold) and benzo[a]pyrene (18-fold) in their capacity to bind to the lymphocyte DNA. The lymphocyte system in combination with the 32P-adduct assay may prove to be an ultrasensitive means to determine interindividual variations in the ability to biotransform carcinogens.

Adenosine Triphosphate↗