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Biomedical subjects

K Krishnan

Publications and source records attributed to K Krishnan.

At least 55 records · Page 3Linked to original sources
PubMed1999

The toxicokinetics of pyrene and its metabolites in rats.

Five experiments were conducted in male Sprague-Dawley rats regarding the kinetic of urinary excretion of 1-hydroxypyrene (1-OHP) following i.v., oral and dermal exposure to 0.5-50 micromol/kg pyrene either as a single substance or as mixture of various polycyclic aromatic hydrocarbons (PAH). Frequent urine collections over 48 h after exposure and a tissue versus time distribution experiment using [14C]pyrene allowed to define the kinetic profile of both pyrene and 1-OHP. For all exposure routes, there is a linear relationship over two orders of magnitude between the dose of pyrene and the urinary excretion of 1-OHP. Differences in biliary/urinary 1-OHP excretion ratio in canulated rats (3) versus faecal/urinary 1-OHP excretion ratio in non-canulated rats (0.6) indicate major enterohepatic recirculation of the metabolite. Half-lives of both pyrene and 1-OHP in all measured tissues were all comprised between 3.1 and 5.4 h, and 5.2-6.7 h, respectively, so that no long term accumulation would be predicted from these values for any tissue. Binary and ternary mixtures involving naphthalene and benzo(a)pyrene in addition to pyrene has no influence on the urinary excretion profile of 1-OHP. All these observations led to the proposal of a dynamic compartment model of pyrene and metabolite flows indicating that following rapid initial distribution to fatty tissues, pyrene is rapidly biotransformed into various metabolites and undergoes major enterohepatic recycling. Part of the initially formed and part of the recirculated 1-OHP eventually undergoes urinary excretion such that close to 60% of pyrene is eliminated as metabolites in urine by 24 h after injection while 20% is excreted in the faeces over the same period.

Administration, Oral↗
PubMed1999

A modeling approach to account for toxicokinetic interactions in the calculation of biological hazard index for chemical mixtures.

Biological hazard index (BHI) is defined as biological level tolerable for exposure to mixture, and is calculated by an equation similar to the conventional hazard index. The BHI calculation, at the present time, is advocated for use in situations where toxicokinetic interactions do not occur among mixture constituents. The objective of this study was to develop an approach for calculating interactions-based BHI for chemical mixtures. The approach consisted of simulating the concentration of exposure indicator in the biological matrix of choice (e.g. venous blood) for each component of the mixture to which workers are exposed and then comparing these to the established BEI values, for calculating the BHI. The simulation of biomarker concentrations was performed using a physiologically-based toxicokinetic (PBTK) model which accounted for the mechanism of interactions among all mixture components (e.g. competitive inhibition). The usefulness of the present approach is illustrated by calculating BHI for varying ambient concentrations of a mixture of three chemicals (toluene (5-40 ppm), m-xylene (10-50 ppm), and ethylbenzene (10-50 ppm)). The results show that the interactions-based BHI can be greater or smaller than that calculated on the basis of additivity principle, particularly at high exposure concentrations. At lower exposure concentrations (e.g. 20 ppm each of toluene, m-xylene and ethylbenzene), the BHI values obtained using the conventional methodology are similar to the interactions-based methodology, confirming that the consequences of competitive inhibition are negligible at lower concentrations. The advantage of the PBTK model-based methodology developed in this study relates to the fact that, the concentrations of individual chemicals in mixtures that will not result in a significant increase in the BHI (i.e. > 1) can be determined by iterative simulation.

Animals↗
PubMed1999

Influence of oral administration of a quaternary mixture of trihalomethanes on their blood kinetics in the rat.

Trihalomethanes (THMs; chloroform, bromoform, bromodichloromethane, dibromochloromethane), formed as by-products of chlorine disinfection, are found to occur in combination in drinking water supplies. THMs are metabolized by cytochromes P-450 and are likely substrates of CYP2E1. Therefore, it is possible that mixed exposure results in toxicokinetic interactions among THMs. The toxicokinetics of THMs during mixed exposures has not been investigated previously. The purpose of this study was to characterize the blood kinetics of the four THMs administered singly or in combination in the rat. A single dose of 0.25 mmol/kg or 0.5 mmol/kg b.w., of each THM alone, or of a quaternary mixture containing 0.25 mmol/kg of each THM (total dose of 1.0 mmol/kg) was administered by gavage. The venous blood concentrations of the THMs were measured by headspace gas chromatography (GC) at 20, 40, 60, 120, 180, 270 and 360 min post-administration. Results showed a nonlinear relationship between the area under the blood concentration versus time curves (AUCs) and administered doses of THMs, suggesting that metabolism is saturated in this dose range. The venous blood concentrations of THMs following administration of the quaternary mixture were significantly higher compared to single exposures. The altered kinetics of THMs during combined exposures is consistent with the occurrence of mutual inhibition of their hepatic metabolism. Simulation exercises conducted with physiologically based toxicokinetic models support metabolic inhibition as the possible mechanism of the interaction among THMs. The data reported in this study provide the starting point for evaluating the significance of interactions among THMs in the risk assessment process.

Administration, Oral↗
PubMed1998

Identification of amino acid residues critical for the Src-homology 2 domain-dependent docking of Stat2 to the interferon alpha receptor.

The interaction between Src-homology 2 domains (SH2) domains and phosphorylated tyrosine residues serves a critical role in intracellular signaling. In addition to the phosphotyrosine, adjacent residues are critical mediators of the specificity of this interaction. Upon treatment of cells with interferon alpha (IFNalpha), the IFNaR1 subunit of the IFNalpha receptor becomes tyrosine phosphorylated at position 466. The region surrounding phosphorylated tyrosine 466 subsequently acts as a docking site for the SH2 domain of Stat2, facilitating phosphorylation of the latter and, thus, the transduction of the IFNalpha signal. In this report site-specific mutagenesis was employed to analyze the nature of the interaction between the SH2 domain of Stat2 and the region surrounding tyrosine 466 on IFNaR1. Mutation of the valine at the +1 position carboxyl-terminal to tyrosine 466 or of the serine at the +5 position inhibits the association of Stat2 with phosphorylated IFNaR1. Moreover, receptors mutated at either of these two positions act in a dominant manner to decrease IFNalpha signaling, as assayed by both Stat2 phosphorylation and expression of an IFNalpha-responsive reporter. The demonstration that these two residues are critical in mediating the interaction between Stat2 and IFNaR1 suggests that STAT proteins might utilize a structurally distinct subset of SH2 domains to mediate signal transduction from the cell surface to the nucleus.

CD4 Antigens↗
PubMed1998

Definition of the interferon-alpha receptor-binding domain on the TYK2 kinase.

Interferons and cytokines modulate gene expression via a simple, direct signaling pathway containing receptors, JAK tyrosine kinases, and STAT transcription factors. The interferon-alpha pathway is a model for these cascades. Two receptors, IFNaR1 and IFNaR2, associate exclusively in a constitutive manner with two JAK proteins, TYK2 and JAK1, respectively. Defining the molecular interface between JAK proteins and their receptors is critical to understanding the signaling pathway and may contribute to the development of novel therapeutics. This report defines the IFNaR1 interaction domain on TYK2. In vitro binding studies demonstrate that the amino-terminal half of TYK2, which is approximately 600 amino acids long and contains JAK homology (JH) domains 3-7, comprises the maximal binding domain for IFNaR1. A fragment containing amino acids 171-601 (JH3-6) also binds IFNaR1, but with reduced affinity. Glutathione S-transferase-TYK2 fusion proteins approximating either the JH6 or JH3 domain affinity-precipitate IFNaR1, suggesting that these are major sites of interaction within the larger binding domain. TYK2 amino acids 1-601 act in a dominant manner to inhibit the transcription of an interferon-alpha-dependent reporter gene, presumably by displacing endogenous TYK2 from the receptor. This same fragment inhibits interferon-alpha-dependent tyrosine phosphorylation of TYK2, STAT1, and STAT2.

Binding Sites↗
PubMed1998

Kinetics of tissue distribution and elimination of pyrene and 1-hydroxypyrene following intravenous administration of [14C]pyrene in rats.

The tissue distribution and elimination of pyrene and 1-hydroxypyrene (1-OHP) were evaluated in male Sprague-Dawley rats (210-240 g) following an intravenous injection of 50 micromol/kg of [14C]pyrene. Blood and tissues were removed and urine and feces were collected at 1, 2, 4, 8, 16, and 24 h postdosing. [14C]Pyrene equivalents were measured by liquid scintillation counting, and beta-glucuronidase/arylsulfatase-treated blood, tissues, and excreta were analyzed for pyrene and 1-OHP by HPLC/fluorescence. At 1 h, the largest fraction of the dose was found in adipose tissue, essentially as pyrene, and its elimination followed first-order monophasic kinetics with a half-life (t(1/2)) of 4.9 h. In blood, liver, kidney, lung, muscle, and gastrointestinal (GI) tract, kinetics of [14C]pyrene equivalents were biphasic and average t(1/2) values for the terminal elimination phase (8 to 24 h) ranged between 6.2 and 8.7 h. Elimination of pyrene in blood and these tissues except the GI tract followed first-order biphasic kinetics with average t(1/2) values of the terminal phase ranging between 3.6 and 5.4 h. In the GI tract, a monophasic elimination kinetics of pyrene was observed with mean t(1/2) value of 3.1 h. Kinetics of 1-OHP in blood and liver showed a monophasic elimination with mean t(1/2) values of 6.7 and 6.2 h, respectively. Kinetics of 1-OHP in the other tissues were biphasic with average t(1/2) values of the terminal elimination phase ranging between 5.2 and 6.2 h. At 24 h, on average, 81.7% of the dose was recovered in the urine (57.2%), feces (18.3%), and GI tract (6.2%) as [14C]pyrene equivalents with 2.7 and 1.9% of dose excreted as total 1-OHP in urine and feces, respectively. At all time points, 1-OHP in urine represented a constant fraction of total 14C in urine and feces. These results indicate that (i) [14C]pyrene was rapidly distributed, metabolized, and eliminated from the body, and (ii) although 1-OHP represents a small percentage of total pyrene eliminated from the body, it remains a reliable indicator of systemic exposure to, and overall elimination of the 14C associated with, this polycyclic aromatic hydrocarbon.

Animals↗
PubMed1998

Cancer chemoprevention. A new way to treat cancer before it happens.

Cancer chemoprevention uses noncytotoxic drugs or nutrients to prevent, retard, or delay carcinogenesis. The future of cancer chemoprevention depends on understanding key cellular growth and proliferation-controlling events, developing markers of molecular carcinogenesis, surrogate endpoint biomarkers, and targeted chemopreventive approaches.

Anticarcinogenic Agents↗
PubMed1998

Clinical models of chemoprevention for colon cancer.

Colon cancer is a common malignancy in the westernized world and is incurable in its advanced stages. This article summarizes the currently available information on colorectal cancer chemoprevention. A brief outline of the incidence and etiologic factors is followed by a discussion of the evidence on which chemopreventive strategies for colon cancer are modeled. This includes a description of the development of surrogate endpoint biomarkers and experimental models to study colorectal cancer chemopreventives, a review of the promising colorectal cancer chemopreventives, and a discussion of the issues to be addressed in the design of future chemoprevention trials. The article concludes with an emphasis on the development and validation of biomarkers and selection of high-risk cohorts using genetic and epidemiologic tools as the main goals of future colon cancer chemoprevention trials before large-scale, risk-reduction trials are conducted.

Animals↗
PubMed1998

Direct interaction of Jak1 and v-Abl is required for v-Abl-induced activation of STATs and proliferation.

In Abelson murine leukemia virus (A-MuLV)-transformed cells, members of the Janus kinase (Jak) family of non-receptor tyrosine kinases and the signal transducers and activators of transcription (STAT) family of signaling proteins are constitutively activated. In these cells, the v-Abl oncoprotein and the Jak proteins physically associate. To define the molecular mechanism of constitutive Jak-STAT signaling in these cells, the functional significance of the v-Abl-Jak association was examined. Mapping the Jak1 interaction domain in v-Abl demonstrates that amino acids 858 to 1080 within the carboxyl-terminal region of v-Abl bind Jak1 through a direct interaction. A mutant of v-Abl lacking this region exhibits a significant defect in Jak1 binding in vivo, fails to activate Jak1 and STAT proteins, and does not support either the proliferation or the survival of BAF/3 cells in the absence of cytokine. Cells expressing this v-Abl mutant show extended latency and decreased frequency in generating tumors in nude mice. In addition, inducible expression of a kinase-inactive mutant of Jak1 protein inhibits the ability of v-Abl to activate STATs and to induce cytokine-independent proliferation, indicating that an active Jak1 is required for these v-Abl-induced signaling pathways in vivo. We propose that Jak1 is a mediator of v-Abl-induced STAT activation and v-Abl induced proliferation in BAF/3 cells, and may be important for efficient transformation of immature B cells by the v-abl oncogene.

Animals↗
PubMed1998

Isolated pancreatic extramedullary hematopoiesis.

A 59-year-old man with lung cancer, peripheral blood leukocytosis and thrombocytosis without peripheral lymphadenopathy and hepatosplenomegaly was found to have pancreatic extramedullary hematopoiesis (EMH) in association with an 'atypical' myeloproliferative disorder. Studies for the Philadelphia chromosome and bcr-abl fusion product were negative. This is the first documented case in the literature of isolated EMH in the pancreas.

Aged↗
PubMed1998

Physiological modeling of toxicokinetic interactions: implications for mixture risk assessment.

Most of the available data on chemical interactions have been obtained in animal studies conducted by administering high doses of chemicals by routes and scenarios different from anticipated human exposures. A mechanistic approach potentially useful for conducting dose, scenario, species, and route extrapolations of toxic interactions is physiological modeling. This approach involves the development of mathematical descriptions of the interrelationships among the critical determinants of toxicokinetics and toxicodynamics. The mechanistic basis of the physiological modeling approach not only enables the species, dose, route, and scenario extrapolations of the occurrence of toxicokinetic interactions but also allows the extrapolation of the occurrence of interactions from binary to multichemical mixtures. Examples are presented to show the feasibility of predicting changes in toxicokinetics of the components of complex chemical mixtures based on the incorporation of binary interaction data within physiologically based models. Interactions-based mixture risk assessment can be performed by simulating the change in the tissue dose of the toxic moiety of each mixture component during combined exposures and calculating the risk associated with each tissue dose estimate using a tissue dose versus response curve for all components. The use of such a mechanistic approach should facilitate the evaluation of the magnitude and relevance of chemical interactions in assessing the risks of low-level human exposures to complex chemical mixtures.

Algorithms↗
PubMed1997

Suppression of human colorectal mucosal prostaglandins: determining the lowest effective aspirin dose.

BACKGROUND: A variety of studies have supported the finding that regular intake of aspirin (acetylsalicylic acid) or nonsteroidal anti-inflammatory agents can affect colorectal cancer carcinogenesis. These agents inhibit the synthesis of prostaglandins. High levels of prostaglandins are observed in colon cancer tissues. PURPOSE: Experiments were planned to determine the lowest dose of aspirin that can markedly suppress the levels of mucosal prostaglandins E2 and F(2alpha) in colorectal mucosa and to determine whether a relationship exists between these levels and plasma levels of both acetylsalicylic acid and its metabolite, salicylic acid. METHODS: Healthy men and women aged 18 years or older participated in the study. The participants took a single, daily dose of aspirin (40.5, 81, 162, 324, or 648 mg) or a placebo for 14 days. Colorectal biopsy specimens were taken at baseline, 24 hours after the first dose of aspirin, and 24-30 hours and 72-78 hours after the last, i.e., fourteenth, daily dose of aspirin. The biopsy specimens were assayed for prostaglandins E2 and F(2alpha) by use of a competitive enzyme immunoassay. Plasma concentrations of acetylsalicylic acid and salicylic acid were determined by use of high-performance liquid chromatography. All P values are two-sided. RESULTS: A total of 65 subjects (10 receiving placebo, groups of 10 each receiving 40.5, 81, 162, or 324 mg of aspirin, and a group of 15 receiving 648 mg of aspirin) completed the protocol. One subject reported unacceptable drug-induced toxic effects and did not complete the protocol; other subjects reported acceptable side effects. The lowest dose to significantly suppress colorectal mucosal prostaglandin E2 concentrations from baseline at 24 hours after the first dose (by 22.6%; P = .002) and at 24-30 hours after the last dose (by 14.2%; P = .021) was 162 mg. At 72-78 hours after the last dose, there was significant suppression for subjects receiving 81 mg (by 23.7%; P = .008). The lowest dose to significantly suppress colorectal mucosal prostaglandin F(2alpha) concentrations from baseline at 24 hours after the first dose (by 18.3%; P = .032) was 324 mg. The lowest dose causing a marked reduction in the level of prostaglandin F(2alpha) at 24-30 hours (by 15.1%; P = .003) and 72-78 hours (by 23.0%; P = .0002) after the last dose was 40.5 mg. No detectable amounts of acetylsalicylic acid or salicylic acid were present in the plasma at any of the biopsy time points. CONCLUSIONS: The lowest doses of aspirin taken daily for 14 days to significantly suppress concentrations of colorectal mucosal prostaglandins E2 and F(2alpha) were 81 and 40.5 mg, respectively. The suppression occurred without detectable amounts of aspirin or salicylic acid in the plasma at the time points studied. On the basis of these observations, we recommend a single, daily dose of 81 mg of aspirin in future studies of this drug as a chemopreventive agent for colorectal cancer.

Adult↗
PubMed1997

Kinase-deficient forms of Jak1 and Tyk2 inhibit interferon alpha signaling in a dominant manner.

Signaling by interferon alpha (IFN alpha), an extracellular factor that mediates a number of anti-viral and growth-suppressive effects, requires two members of the Janus family of tyrosine kinases (JAK family): Jak1 and Tyk2. IFN alpha treatment of cells induces the rapid tyrosine phosphorylation of these two kinases, two subunits of the IFN alpha receptor, and two members of the signal transducer and activator of transcription (STAT) family of latent transcription factors. These proteins are believed to be direct substrates of one or both JAKs. Though the requirement for both Jak1 and Tyk2 in the IFN alpha-signaling cascade is well established, the order of activation and the relative contribution of the two kinases has not been elucidated completely. To address these questions, we have employed kinase-deficient mutants of both enzymes. Both mutant kinases suppress transcriptional activation as measured by an IFN alpha-dependent reporter-gene assay. Furthermore, in transient-transfection assays, the kinase-deficient versions of Tyk2 and Jak1 can act independently to inhibit STAT phosphorylation. Thus, kinase-deficient versions of JAK can act in a dominant-negative fashion to suppress IFN alpha signaling. The effects of the overexpressed mutant kinases on the phosphorylation of the kinases themselves, however, are unequal, suggesting that Jak1 functions upstream of Tyk2.

Cells, Cultured↗
PubMed1997

Characterization of methemoglobinemia induced by 3,5-xylidine in rats.

The objective of this study was to characterize the dose effect and kinetics of methemoglobinemia in rats following oral or intravenous administration of 3,5-xylidine (XYL). The first set of experiments involved the intravenous administration of 0.06, 0.12, 0.24, 0.48, or 0.60 mmol XYL/kg to groups of 3 rats each and the serial sampling of blood from the tail vein of individual animals for the determination of methemoglobin levels. An additional series of experiments involved the oral administration of 0.24, 0.48, 0.72, 0.96, 1.2, 1.8, 2.4, or 4.8 mmol XYL/kg and the serial sampling of blood for the determination of methemoglobin levels. The results showed a dose-dependent induction of methemoglobinemia by XYL in the rat, for both routes of administration. The maximal percent methemoglobin observed in the treated animals was 28.90 +/- 0.34% and 32.67 +/- 2.14% for the intravenous (0.6 mmol/kg) and oral (4.8 mmol/kg) routes, respectively. The dose levels of 0.06 mmol/kg (iv) and 0.96 mmol/kg (po) were the no-observable-adverse-effect levels with respect to XYL-induced methemoglobinemia in the rat. The dose-effect information on XYL-induced methemoglobinemia obtained in this study may be useful for the characterization of noncarcinogenic risks of acute human exposure to this chemical.

Administration, Oral↗
PubMed1997

Assessing the relevance of rodent data on chemical interactions for health risk assessment purposes: a case study with dichloromethane-toluene mixture.

Several descriptive studies have reported the occurrence of infra-additive and supra-additive toxic interactions in rodents given high doses of chemicals by routes different from anticipated human exposures. In order to assess the relevance of such rodent data on chemical interactions for humans, the route, species, and dose extrapolations need to be conducted on the basis of proven/hypothetical interaction mechanisms. The present study initially developed a physiologically based model of the toxicological interaction reported in rats receiving high oral doses of dichloromethane (DCM) and toluene (TOL). This predictive model was then used to asses the relevance of DCM-TOL interaction for humans exposed to threshold limit values (TLVs) of these chemicals, following the conduct of the various, essential extrapolations (i.e., rat to human, oral to inhalation, high dose to low dose). The interaction modeling approach involved (i) obtaining validated rat and human physiologically based pharmacokinetic (PBPK) models for TOL and DCM from the literature, and (ii) linking them via the modified Michaelis-Menten equation accounting for hypothetical mechanisms of interactions (no interaction, competitive inhibition, noncompetitive inhibition, and uncompetitive inhibition). Of the various interaction mechanisms investigated, the noncompetitive and uncompetitive metabolic inhibitions were found to adequately describe the reduction of carboxyhemoglobinemia (COHB) observed in rats during combined exposures (18.8 mmol/kg TOL, +6.2 mmol/kg DCM, po; 0.005 mmol/kg TOL, ip +5000 ppm DCM, 1 hr). The simulation model, based on noncompetitive and uncompetitive inhibition mechanisms, suggests that only < 10% reduction in the area under the COHB vs time curve (AUCCOHB) is likely to occur in humans exposed to the current TLVs of DCM and TOL (compared to AUCCOHB resulting from an 8-hr exposure to TLV of DCM alone). The present modeling approach, based on hypothetical mechanisms of interaction, then indicates that rodent data on DCM-TOL interaction are not relevant for humans, particularly with respect to the COHB effect. The application of this kind of a predictive modeling approach should be useful in screening the available reports on chemical interactions for identifying those of greater concern at relevant human exposure levels (RfD, RfC, TLV).

Administration, Inhalation↗