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Biomedical subjects

K Krishnan

Publications and source records attributed to K Krishnan.

At least 109 records · Page 6Linked to original sources
PubMed1994

Hb Washtenaw [ beta 11(A8)Val-->Phe]: an electrophorectically silent, unstable, low oxygen affinity variant associated with anemia and chronic cyanosis.

Hb Washtenaw [beta 11(A8)Val-->Phe] is a new, low oxygen affinity variant with a previously undescribed substitution, identified in seven members over three generations of a Hungarian-American family. The hemoglobin is mildly unstable and the family members studied are clinically asymptomatic but mildly cyanotic, and some exhibit mild anemia. The index case had severe pulmonary hypertension and some of the family members had increased pulmonary vascular resistance on echocardiography. An association between the inheritance of this abnormal hemoglobin and the pathogenesis of primary pulmonary hypertension is suggested but the mechanism is unclear.

Adolescent↗
PubMed1993

Inhibitors of mitochondrial carnitine palmitoyltransferase I limit the action of proteases on the enzyme. Isolation and partial amino acid analysis of a truncated form of the rat liver isozyme.

Our objective was to isolate from rat liver mitochondria the malonyl-CoA-regulated and detergent-labile enzyme, carnitine palmitoyltransferase I (CPT I), whose properties and relationship to CPT II have been the subject of debate. After exposure of mitochondria to the dinitrophenol derivative of etomoxir-CoA (DNP-Et-CoA, a covalent inhibitor of CPT I), followed by detergent solubilization and blue Sepharose chromatography, the DNP-Et-labeled CPT I could be readily visualized on immunoblots using an anti-DNP monoclonal antibody. This material was used to raise a rabbit polyclonal antibody that recognized CPT I regardless of whether it was carrying a covalent ligand. Exposure of membranes from untreated mitochondria to a mixture of trypsin and chymotrypsin caused rapid loss of CPT I activity with a concomitant disappearance of immunodetectable protein. However, inclusion of malonyl-CoA in such incubations afforded major protection of CPT I activity. Under these conditions CPT I simply underwent truncation from approximately 90 to approximately 82 kDa. This was also true if CPT I had first been labeled with Et-CoA or DNP-Et-CoA prior to protease treatment. Thus, the presence of an inhibitor, whether reversible or irreversible, at the active site of CPT I limited the action of trypsin/chymotrypsin to removal of a small portion of the protein which was probably not necessary for catalytic function. These and other experiments with antibodies and proteases provided additional insight into the membrane topology of CPT I. They also strengthened our conviction that CPT I and CPT II are distinct proteins and that the former exists as tissue-specific isoforms. Finally, the 82-kDa truncated form of rat liver CPT I was isolated and subjected to partial amino acid analysis. Four unambiguous peptide sequences were obtained.

Acyl Coenzyme A↗
PubMed1993

Physiologically based modeling of the toxicokinetic interaction between toluene and m-xylene in the rat.

The present study was undertaken to investigate the mechanism of toxicokinetic interaction between toluene (TOL) and m-xylene (XYL) in vivo in the male Sprague-Dawley rat by physiologically based toxicokinetic (PBTK) modeling. First, the metabolic constants (Vmax and Km) were determined for TOL and XYL individually by conducting a series of closed-chamber inhalation exposures of three rats to starting concentrations of 500 to 4000 ppm. The values of Km (TOL, 0.55 mg/liter; XYL, 0.20 mg/liter) and Vmax (TOL, 4.8 mg/hr/kg; XYL, 8.4 mg/hr/kg) were obtained following best visual fit of PBTK model simulations to experimental data. Then using the same experimental set-up, rats were exposed to three different mixtures of both solvents (500 ppm TOL + 1000 ppm XYL; 1000 ppm TOL + 1000 ppm XYL; 1000 ppm TOL + 500 ppm XYL). The data from the time course of chamber solvent concentrations were analyzed with a binary chemical mixture PBTK model that had four mechanistic hypotheses of metabolic interaction (i.e., no interaction, competitive inhibition, noncompetitive inhibition, and uncompetitive inhibition) quantitatively defined in the liver compartment. The validity of the various model descriptions was verified with open-chamber inhalation exposure data on toxicokinetics of TOL and XYL. Overall, the results of this combined experimental and modeling approach are consistent with a competitive metabolic inhibition between XYL and TOL in the rat.

Animals↗
PubMed1993

A descriptive and mechanistic study of the interaction between toluene and xylene in humans.

This study was undertaken to characterize the mechanism of toxicokinetic interaction between toluene (TOL) and m-xylene (XYL) in the rat using physiologically-based toxicokinetic (PBTK) modeling approach. First, the metabolic rate constants were determined by conducting closed-chamber inhalation exposures with individual solvents (Vmax: TOL = 4.8, XYL = 8.4 mg/hr/kg; Km: TOL = 0.55, XYL = 0.2 mg/l). Then, using the same experimental set-up, rats were exposed to different binary mixtures of TOL and XYL. PBTK analysis of the data showed competitive inhibition as the plausible mechanism of TOL/XYL interaction. This mechanistic modeling study suggests that the interaction between TOL and XYL is likely to be observed when the exposure concentration exceeds 50 ppm of each solvent.

Animals↗
PubMed1993

Catamenial haemoptysis: a rare cause.

Since the first report of pulmonary endometriosis as a cause of catamenial haemoptysis all cases have been assumed to be due to pulmonary endometriosis, even in the absence of histopathological proof. A case is presented where the histological findings were of a pulmonary arteriovenous malformation.

Adult↗
PubMed1992

Biologically based modeling in toxicology research.

Biologically based modeling can be described as the process by which the specific mechanistic steps governing tissue disposition and toxic action of chemicals are expressed in quantitative terms by a set of equations leading to prediction of the outcome of specific toxicological experiments by computer simulation. These models are useful in risk assessment because their mechanistic biological basis permits the high-to-low dose, route to route and interspecies extrapolation of the tissue disposition and toxic action of chemicals. By far their greatest utility is not as "finished" risk assessment models, but as research tools that convey a quantitative expression of our hypotheses of tissue disposition and toxic action of a chemical. A structured modeling approach to toxicology problems helps identify the data gaps in the areas of chemical disposition and toxic action, thus prioritizing on-going research to obtain critical information required to conduct quantitative risk assessment. This paper examines progress in developing comprehensive biologically based models for cancer induction by non-genotoxic carcinogens that are cytotoxic in target tissues. The strategies for linking the models on dosimetry, cytotoxicity, and carcinogenicity are described in detail. The basic concepts and approaches discussed here can be applied to many other toxic chemicals and to toxicity endpoints other than cancer.

Animals↗
PubMed1992

Modulation of hexachlorobenzene-induced hepatic porphyria by methyl isobutyl ketone in the rat.

Potential toxic interaction between hexachlorobenzene (HCB) and methyl isobutyl ketone (MiBK) was investigated using two different schedules of toxicant administration. The first schedule involved simultaneous administration of HCB (50 mg/kg/d, p.o. in 10 ml/kg corn oil at 10.00 a.m. for 5 d/wk) and MiBK (7.5 mmol/kg/d, p.o. in 10 ml/kg corn oil at 4.00 p.m. for 3 d/wk) for 6 weeks. The second schedule involved an initial dosing of 25 or 50 mg HCB/kg/d for 12 consecutive days, followed by the administration of 7.5 mmol MiBK/kg every other day for 27 days. When administered simultaneously, MiBK reduced the severity of HCB-induced porphyria, but when given sequentially after HCB accumulation, it enhanced the porphyrinogenic response. These results suggest that the effect of combined exposure to HCB and MiBK on hepatic porphyria depends on the sequence of the administration of both chemicals, and that the mechanism involved in this interaction may invoke both the induction and inhibition of specific hepatic isoenzymes by MiBK.

Administration, Oral↗
PubMed1991

Development of an experimental model for the study of hexachlorobenzene-induced hepatic porphyria in the rat.

Hexachlorobenzene (HCB) induces hepatic porphyria in rats. Various protocols of repeated cumulative and daily doses of HCB administered for several weeks until porphyria develops have been traditionally used. In order to undertake studies on early biochemical events occurring in HCB-induced porphyria, we have designed an experimental model involving the administration of a minimal amount of HCB inducing a fully developed porphyria in a well defined and predictable time frame. Groups of Sprague-Dawley rats were given (po, in 10 ml/kg of corn oil) a cumulative dose of 1,500 mg HCB/kg as 50 mg/kg for 6 weeks (5 days/week) or 100 mg/kg for 3 weeks (5 days/week). In female, but not male, rats treated for 6 weeks, HCB caused a porphyria as measured by urinary uroporphyrin and hepatic porphyrin levels; this total dose given to female rats in 3 weeks was not, however, porphyrinogenic. Female rats were given 12 consecutive daily doses of 50 mg HCB/kg followed by a no-treatment period of 30 days; this cumulative dose of 600 mg HCB/kg induced a porphyria after 6 weeks. The approximate minimally effective cumulative dose inducing porphyria was determined to be 400 mg HCB/kg, regardless of the magnitude of the daily dose (25, 50, or 100 mg/kg). Finally, the administration of a cumulative dose of 500 mg HCB/kg (50 mg/kg, 5 days/week for 2 weeks or 100 mg/kg/day for 5 days) induced after 5 to 6 weeks a porphyria that persisted for more than 500 to 600 days.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1982

Radial partition immunoassay.

In radial partition immunoassay, radial chromatography is used for performing an immunoassay. We describe the application of this technology to the measurement of digoxin in serum by enzyme immunoassay, with the entire testing procedure carried out on glass-fiber filter paper. A sample is applied to a small central area of the filter paper, where it reacts with the antibody to digoxin immobilized there. Subsequently, enzyme-labeled digoxin is applied to react with remaining antibody sites. After incubation, substrate for the enzyme is applied to the center of the reaction area and washes out any unbound label to the periphery of the paper. This step also initiates the enzyme reaction, which is quantified by front-surface fluorescence. A microprocessor-controlled automated instrument has been developed to process the filter paper matrix through the above sequence, and calculate the final result. Total testing time for digoxin is less than 7 min.

Antibodies↗
PubMedDate not supplied

In vitro and in vivo evaluations of the methaemoglobinaemic potential of xylidine isomers in the rat.

The objective of the present study was to evaluate the methaemoglobinaemic potential of the six isomers of xylidine (XYL) by two approaches: in vitro, using rat red blood cells and hepatic post-mitochondrial fractions in a two-compartmental dialysis system; and in vivo, following a single oral dose of 4.8 mmol kg(-1) (p.o.) of each of the six XYL isomers. The in vitro experiments showed that all six XYL isomers at 1 mM concentration induced significant methaemoglobinaemia in the presence of active hepatic fractions, whereas non-bioactivated XYL isomers were totally inactive. At lower incubation concentrations (0.3 mM and 0.06 mM), 3,5-XYL was still active, whereas the other isomers were less potent (0.3 mM) or totally ineffective (0.06 mM). The in vivo experiment revealed that all XYL isomers, except 3,5-XYL, did not induce significant methaemoglobinaemia after a single oral dose of 4.8 mmol kg(-1). The maximal percentage of methaemoglobin was 31.3 +/- 1.5 in the 3,5-XYL-treated rats, whereas it never exceeded 3% in all the other treatment groups, indicating that 4.8 mmol kg(-1) (p.o.) is in fact a no-observable-adverse-effect level for these XYL isomers. The quantitative differences between in vivo and in vitro results may have been due to additional bioactivation pathways (N-hydroxylation or ring hydroxylation) mediated by high Km enzymes operative at the high incubation concentrations used in vitro. The results of the present study suggest that 3,5-XYL is likely to be the only active isomer in the Sprague-Dawley rat at low exposure levels.

Administration, Oral↗
PubMedDate not supplied

Urinary excretion kinetics of 1-hydroxypyrene following intravenous administration of binary and ternary mixtures of polycyclic aromatic hydrocarbons in rat.

The effect of exposure to binary and ternary mixtures of polycyclic aromatic hydrocarbons (PAHs) on the urinary excretion kinetics of 1-hydroxypyrene (1-OHP) has been examined. Male Sprague-Dawley rats were administered intravenously 5 micromol/kg of pyrene alone or in combination with 0.5, 5 and 25 micromol/kg of either naphthalene, benzo(a)pyrene (BaP), or both. Urine samples were collected at frequent intervals over 48 h. The kinetics of 1-OHP in urine was not altered by the presence of either naphthalene or BaP in the mixtures, at least from 4 h post-dosing. Hence, none of the injected mixtures significantly modified the first-order apparent elimination half-life of 1-OHP in urine obtained for the 12 to 42 h period post injection where mean values ranged between 6.2 and 9.6 h. However, while the presence of naphthalene or the low BaP dose of 0.5 micromol/kg in the mixtures did not have a significant effect on the total excretion of 1-OHP, BaP doses of 5 and 25 micromol/kg in the mixtures significantly increased the amount of 1-OHP excreted in urine. Mean percentages of the pyrene dose excreted as 1-OHP after injection of pyrene in combination with 0.5, 5 and 25 micromol/kg BaP were respectively increased 1.3, 2.2 and 2.6 times compared to the value obtained after administration of pyrene alone. The percentages determined after concomitant administration of pyrene and 0.5, 5 and 25 micromol/kg of BaP plus naphthalene were 1.4, 1.8 and 2.4 times, respectively, the value obtained after administration of pyrene singly. The observed effect of BaP (5 or 25 micromol/kg) on 1-OHP total excretion appears to result from BaP induction of pyrene metabolism. Lack of effect of naphthalene appears to be due to its weak P450 1A1 enzyme induction capacity. Absence of significant effect of the low BaP dose in the mixtures (0.5 micromol/kg) suggests that 1-OHP in urine is useful as a bioindicator of occupational and environmental exposures to PAH mixtures.

Animals↗