PubMed Health⌕ Search

Biomedical subjects

L S Kaminsky

Publications and source records attributed to L S Kaminsky.

At least 73 records · Page 4Linked to original sources
PubMed1986

Fluorescence probing of the function-specific cysteines of rat microsomal NADPH-cytochrome P-450 reductase.

Titration of NADPH-cytochrome P-450 reductase with a fluorigenic maleimide suggests that approximately four cysteines are initially accessible and in close proximity to four tryptophans. Perturbation of the cysteines and/or tryptophans results in concomitant decreases in enzymic activity. These cysteines were correlated with functional components by binding studies and subsequent tryptic peptide mapping on the acid mobile phase-reverse phase HPLC. Adenine nucleotides and cytochrome c block labelling of the more hydrophilic peptides, while detergents facilitate labelling of the more hydrophobic peptides. The more hydrophobic peptides contain the microsomal binding site of cytochrome P-450. Removal of the prosthetic flavins exposes more cysteines in the more hydrophilic and hydrophobic regions of the peptide map, associating the former with FAD and the latter with FMN binding sites.

Adenine Nucleotides↗
PubMed1986

The effects of Love Canal soil extracts on maternal health and fetal development in rats.

The effects of a solvent extract of the surface soil of the Love Canal chemical dump site, Niagara Falls, New York, and of a natural extract, or leachate, which is drained from the canal for treatment, on the maternal health and fetal development were determined in rats. The solvent extract, which was contaminated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (2, 3,7,8-TCDD) at 170 ppb and numerous other chlorinated organic compounds with the primary identified components being the isomers of benzenehexachloride (BHC), was dissolved in corn oil and administered by gavage to pregnant rats at 0,25,75, or 150 mg crude extract/kg/day on Days 6-15 of gestation. A 67% mortality was observed at the highest dose. The rats were sacrificed on Day 20. Dose-related increases in relative liver weight accompanied by hepatocyte hypertrophy were observed at all dose levels. Fetal birthweight was decreased at 75 and 150 mg extract/kg/day. No major treatment-related soft tissue or skeletal malformations, except for delayed ossification, were observed. Based on literature values for BHC, all of the observed toxicity could be accounted for by the BHC contaminants of the extract. The crude organic phase of the leachate was administered to pregnant rats at 0,10,100, or 250 mg/kg/day as described above. Maternal weight gain decreased at 100 and 250 mg/kg/day, accompanied by 5 and 14% maternal mortality, and 1 and 3 dead fetuses, respectively. Early resorptions and the percentage of dead implants increased whereas fetal birthweights were decreased at 250 mg/kg/day. No major treatment-related soft tissue or skeletal malformations, except for delayed ossification, were observed. The primary components of the complex leachate by mass were tetrachloroethanes; however, 2,3,7,8-TCDD, which was present at 3 ppm, probably accounted for all the observed toxicity.

Abnormalities, Drug-Induced↗
PubMed1986

Subchronic oral toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin in the guinea pig: comparisons with a PCB-containing transformer fluid pyrolysate.

In contrast to the well-characterized acute toxicity of the environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD) in the guinea pig, the effects of prolonged po exposure in this species are unknown. The present report describes the results of administration to guinea pigs of 2,3,7,8-TCDD in the feed at levels of 0, 2, 10, 76, or 430 ppt for up to 90 days. Additional aims were to examine recovery following prolonged 2,3,7,8-TCDD exposure in the guinea pig and to generate data to facilitate comparison of the previously reported toxicity of a transformer fluid pyrolysate with that of pure 2,3,7,8-TCDD. Animals receiving 430 ppt 2,3,7,8-TCDD exhibited body weight loss, thymic atrophy, liver enlargement, and 60% mortality by Day 46 (males) and by Day 60 (females), when surviving animals in this group were sacrificed. Total 2,3,7,8-TCDD consumption was approximately 1.3 and 1.9 micrograms/kg, respectively. Animals receiving 76 ppt 2,3,7,8-TCDD for 90 days (total 0.44 microgram/kg) exhibited a decreased rate of body weight gain and increased relative (to body) liver weights. Male animals also displayed a reduction in relative thymus weights and elevated serum triglycerides, while females exhibited hepatocellular cytoplasmic inclusion bodies and lowered serum alanine aminotransferase activities. Toxic effects were generally similar to those observed after acute 2,3,7,8-TCDD administration. No dose-related alterations were seen in animals receiving either 10 ppt (total 0.06 micrograms/kg) or 2 ppt (total 0.01 micrograms/kg) for 90 days, establishing a no-observed-effect level of approximately 0.65 ng 2,3,7,8-TCDD/kg/day. In the recovery study, groups of guinea pigs were administered 430 ppt 2,3,7,8-TCDD for 11, 21, or 35 days and then allowed to recover for an additional 79, 69, or 55 days, respectively. Treatment-related mortality in each group was 0, 10, and 70%, respectively, by Day 90. An effective LD50 of 0.8 microgram 2,3,7,8-TCDD/kg for prolonged exposure was calculated on the basis of these results, a value lower than those previously reported from this laboratory for acute exposure. The results also suggested a possible lowering of the body weight "set point" following 2,3,7,8-TCDD exposure. Comparison of the present findings with those previously reported for a transformer fluid pyrolysate containing a mixture of polychlorinated aromatic species indicated both a greater variety of toxic effects and flatter dose-response relationships for the pyrolysate in the guinea pig.

Administration, Oral↗
PubMed1986

Absence of antibodies to the human immunodeficiency virus in sera from Africa prior to 1975.

Three different assays for detection of antibodies to the human immunodeficiency virus (HIV) were conducted on 677 sera obtained from 1964 to 1975 from male and female children and adults in Uganda and other countries in Africa. Several sera were collected from individuals with Kaposi sarcoma. No evidence of antibodies to the virus was noted up to 1975. These results strongly suggest that the emergence of HIV in Africa occurred relatively recently. Further studies are required to determine the geographic origin of the acquired immunodeficiency syndrome virus.

Acquired Immunodeficiency Syndrome↗
PubMed1986

AIDS retrovirus antibodies in hemophiliacs treated with factor VIII or factor IX concentrates, cryoprecipitate, or fresh frozen plasma: prevalence, seroconversion rate, and clinical correlations.

Antibodies to the AIDS retrovirus, specifically to human T cell lymphotropic virus, type III, and AIDS-associated retrovirus, were detected with increasing prevalence in a population of 190 hemophiliacs from western Pennsylvania between 1981 and 1984: 7.7% in 1981, 20.0% in 1982, 45.5% in 1983, and 62.5% in 1984. The seropositive included approximately three fourths of those receiving factor VIII concentrate, nearly one third of those receiving factor IX concentrate, nearly one fifth of those receiving cryoprecipitate, and none of those receiving fresh frozen plasma. The seroconversion rate, determined on 43 seropositive hemophiliacs from this group who were serially sampled, was 0% in 1977, 4.7% in 1978, 4.9% in 1979, 2.6% in 1980, 10.5% in 1981, 52.9% in 1982, 87.5% in 1983, and 100% in 1984. Of 27 seropositive for three or more years (since 1982 or before), four (15%) have developed AIDS and seven (26%), diffuse lymphadenopathy (ARC); of 16 seropositive for less than three years, none has developed AIDS and three (19%) have developed ARC. The mean time from seroconversion to onset of ARC, 0.8 +/- 0.2 years (SEM), was shorter (P less than .001) than the time to onset of AIDS, 4.1 +/- 0.6 years. These findings confirm the widespread presence of AIDS retrovirus and support the association of these retroviruses with the acquired immunodeficiency syndrome and related conditions.

Acquired Immunodeficiency Syndrome↗
PubMed1986

Dichloromethyl compounds as mechanism-based inactivators of rat liver cytochromes P-450 in vitro.

Twenty dichloromethyl compounds have been tested as potential mechanism-based inactivators of the major phenobarbital-inducible isozyme of rat liver cytochrome P-450 (PB-B) in a reconstituted system. With the exception of dichloromethane and dichloroacetamide, all the compounds decreased the ethoxycoumarin deethylase activity of the enzyme in a time- and NADPH-dependent manner. The inhibitory compounds could be divided into two classes according to whether the loss of monooxygenase activity was accompanied by a decrease in spectrally detectable cytochrome P-450. N-Monosubstituted dichloroacetamides in which the side-chain consisted of a phenyl or n-octyl group were able to mimic the action of chloramphenicol and inactivate the PB-B without destroying the heme moiety. In contrast, dichloroacetamides containing an n-hexyl, n-butyl, or methyl substituent caused a significant loss of heme, as did the five non-amides tested: 1,1,2,2-tetrachloroethane, 1,1-dichloroacetone, methyl dichloroacetate, alpha,alpha-dichlorotoluene, and alpha,alpha-dichloroacetophenone. Representative compounds were also examined as inactivators of the major beta-naphthoflavone-inducible isozyme of rat liver cytochrome P-450 (BNF-B), using a reconstituted system, as well as of constitutive cytochromes P-450, using intact liver microsomes from untreated rats. These studies suggested a marked difference in isozyme selectivity between certain of the compounds. For example, of the isozymes monitored, only the PB-B was affected by alpha,alpha-dichlorotoluene in an NADPH-dependent manner, whereas N-octyl dichloroacetamide inactivated not only the PB-B and BNF-B, but also certain constitutive cytochromes, as evidenced by decreases in microsomal S-warfarin hydroxylase activities. These studies help delineate the structural requirements for the use of dichloromethyl compounds as probes of cytochrome P-450 function and as potential isozyme-selective inhibitors.

Acetamides↗
PubMed1985

Cytochrome P-450 isozyme/isozyme functional interactions and NADPH-cytochrome P-450 reductase concentrations as factors in microsomal metabolism of warfarin.

The basis for our previous observations [Kaminsky, L.S., Guengerich, F.P., Dannan, G.A. & Aust, S.D. (1983) Arch. Biochem. Biophys. 225, 398-404] that rates of microsomal metabolism of warfarin were markedly less than the sum of rates of the reconstituted constituent isozymes of cytochrome P-450 has been investigated. Metabolism of warfarin to 4'-, 6-, 7-, 8-, and 10-hydroxywarfarin and dehydrowarfarin by highly purified rat liver cytochrome P-450 (P-450) isozymes reconstituted with NADPH-cytochrome P-450 reductase and by hepatic microsomes from variously pretreated rats was used to probe functional consequences of P-450 isozyme/isozyme interactions and of the effect of microsomal reductase concentrations. Binary mixtures of P-450 isozymes were reconstituted and the regioselectivity and stereoselectivity were used to probe metabolism by each individual isozyme. The isozymes specifically inhibited each other to variable extents and the order of inhibitory potency was: P-450UT-F greater than P-450PB-D greater than or equal to P-450UT-A greater than or equal to P-450BNF/ISF-G greater than P-450PB/PCN-E greater than P-450PB-B greater than or equal to P-450PB-C greater than or equal to P-450BNF-B. The inhibition, possibly a consequence of aggregation, explains the low rate of microsomal metabolism relative to the metabolic potential of the component P-450 isozymes. When purified reductase was added to microsomes it appeared to bind to microsomes at different sites from endogenous reductase and it enhanced warfarin hydroxylase activity only to a minor extent, thus possibly precluding low reductase concentrations from being a major factor in the relatively low rates of microsomal metabolism. Antibody to the reductase differentially inhibited microsomal metabolism of warfarin by the various P-450 isozymes. The results suggest that the reductase and P-450 isozymes may be located differently relative to one another in the various microsomal preparations.

Animals↗
PubMed1985

High prevalence of antibodies to acquired immune deficiency syndrome (AIDS)-associated retrovirus (ARV) in AIDS and related conditions but not in other disease states.

A rapid, sensitive indirect immunofluorescence assay has been developed for detection of antibodies to the acquired immune deficiency syndrome (AIDS)-associated retrovirus (ARV). The human T-cell line HUT-78 was chronically infected with ARV-2 and used to detect antibodies to virus-specific cytoplasmic antigens. Because the helper T-cell marker Leu-3 is substantially reduced in this cell line after ARV infection, it appears to be an important receptor for virus infection. Nearly all patients with AIDS and most cases with related conditions showed antibodies against ARV. Some healthy individuals in risk groups for developing AIDS also had antibodies to the agent. In contrast, no antibodies to the virus were found in any individuals outside the risk groups for developing AIDS or with diseases other than those associated with AIDS. The titers of antibodies to ARV and to Epstein-Barr virus varied independently from each other. The level of anti-ARV antibodies in a patient's serum was found to reflect the severity of the disease; it was lower in individuals with more severe manifestations. Taken together, these data support the role of ARV in AIDS and its related disorders.

Acquired Immunodeficiency Syndrome↗
PubMed1985

Chemical and biological investigations of a transformer accident at Binghamton, NY.

A transformer fire occurred in a state office building in Binghamton, NY on February 5, 1981. Particulates from inside surfaces of ceiling panels on 16 of the 17 floors had concentrations of polychlorinated dibenzofurans (PCDFs) ranging from less than 1 part per million (ppm) to 1200 ppm while polychlorinated biphenyl (PCB) concentrations varied from 28 ppm to 23,000 ppm. In spite of the wide variations in contaminant concentrations, complete analytical data from 11 floors showed that there was a consistent PCDF/PCB ratio (0.067 +/- 0.026) and also consistent PCDF isomer group distributions (tetra-CDFs, 33 +/- 5%; penta-CDFs, 40 +/- 3%; hexa-CDFs, 18 +/- 7%; hepta-CDFs, 6 +/- 3%). It was found that the particulate samples could be successfully ranked in order of their degree of chemical contamination by an in vitro bioassay. The bioassay was based on induction of keratinization or changes in morphology in mouse epithelial cells. Animal toxicology experiments were carried out with a soot sample containing a PCDF concentration which approximated the mean value found on the ceiling particulates. The single dose oral LD values of the soot and its benzene extract equivalent, each administered to female guinea pigs in 0.75% methyl cellulose, were 410 and 327 mg/kg, respectively. These results demonstrated that the soot matrix had virtually no effect on the toxicity of the chemical contaminants in the soot. Morphological alterations in liver tissues from animals receiving the soot were found after examination by electron and light microscopy.(ABSTRACT TRUNCATED AT 250 WORDS)

Accidents, Occupational↗
PubMed1985

Infection by the retrovirus associated with the acquired immunodeficiency syndrome. Clinical, biological, and molecular features.

Peripheral mononuclear cells from more than 160 persons from groups at risk for the acquired immunodeficiency syndrome (AIDS) have yielded AIDS-associated retroviruses (ARV). Antibodies to ARV can also be found in these risk groups. Antibody-negative, virus-positive persons have been identified with early infection or possible viremia with immune complex formation. Established lines of human T and B cells, monocytes, and promyelocytes have been infected with ARV. Moreover, infectious virus has been recovered from macrophages cultured from the blood of some persons with AIDS. The cytopathic effects of ARV in T cells is associated with the accumulation of unintegrated viral forms in the infected cells. The ARV has also been isolated from plasma, serum, saliva, semen, urine, cerebrospinal fluid, and brain tissue. All these results reflect the wide host range of ARV and support its role in neurologic abnormalities seen in some patients. Molecular studies of independent ARV isolates indicate a polymorphism of nucleotide sequences, particularly in the viral envelope region. All these features place ARV in the lentivirus subfamily of human retroviruses.

Acquired Immunodeficiency Syndrome↗
PubMed1985

Isozyme selectivity of the inhibition of rat liver cytochromes P-450 by chloramphenicol in vivo.

The isozyme-selectivity of chloramphenicol as an inhibitor of rat liver cytochromes P-450 has been investigated. Untreated rats and rats treated with the inducers phenobarbital, beta-naphthoflavone, pregnenolone 16 alpha-carbonitrile, and clofibrate have been injected intraperitoneally with chloramphenicol, and inhibition of specific cytochrome P-450 isozymes has been assessed by monitoring the metabolism of warfarin, testosterone, isosafrole, or lauric acid in subsequently prepared hepatic microsomal preparations. Of eight major cytochrome P-450 isozymes which could be monitored in this fashion, three were inhibited by more than 50% by a dose of chloramphenicol of 300 mg/kg, whereas no evidence of inhibition of the remaining isozymes was obtained. P-450PB-C, an isozyme which is present in significant amounts in untreated rats and which is induced approximately 2-fold by phenobarbital, was the most susceptible cytochrome P-450 to inhibition by chloramphenicol both in vivo and in vitro. P-450PB-B, the major phenobarbital-inducible isozyme, and P-450UT-A, a male-specific testosterone 2 alpha- and 16 alpha-hydroxylase, were intermediate in their susceptibility to chloramphenicol. In contrast, the major isozymes induced by beta-naphthoflavone, pregnenolone 16 alpha-carbonitrile, and clofibrate, as well as a constitutive testosterone 7 alpha-hydroxylase, were not inhibited by chloramphenicol.

Animals↗
PubMed1984

AIDS and related conditions. One year's experience in St. Vincent's Hospital, Sydney.

Fifty-six patients were referred in 1983 for assessment in connection with AIDS and related disorders. Clinical and immunological classification of patients was carried out according to the NHMRC criteria. The presence of antibodies to an AIDS-associated retrovirus (ARV) was determined in some patients. Of the 32 patients who could be categorized, three patients had AIDS, and all three had serum antibodies to ARV. Fifteen patients had lymphadenopathy syndrome with impaired T-cell immunity. Ten of 12 patients tested had antibodies to ARV. Symptomatic illnesses resembling lymphadenopathy syndrome, but without immune defects, occurred in nine patients. By contrast, five patients who had no symptoms had impaired immunity, and in seven patients no clinical and immunological abnormalities were found. The classification proposed by the NHMRC was found to be useful in delineating several major clinical and immunological patterns of response to infection with the AIDS-associated retrovirus.

Acquired Immunodeficiency Syndrome↗
PubMed1984

Contact tracing in the acquired immune deficiency syndrome (AIDS). Evidence for transmission of virus and disease by an asymptomatic carrier.

The sexual contacts of a patient with acquired immune deficiency syndrome were traced, and clinical, immunological, and serological evidence was obtained and evaluated. It was determined that the patient acquired the disease from a homosexual man who had no symptoms, but in whom laboratory evidence of immunodeficiency and serological evidence of exposure to the AIDS-associated retrovirus was found.

Acquired Immunodeficiency Syndrome↗
PubMed1984

Composition of cytochrome P-450 isozymes from hepatic microsomes of C57BL/6 and DBA/2 mice assessed by warfarin metabolism, immunoinhibition, and immunoelectrophoresis with anti-(rat cytochrome P-450).

The composition of isozymes of hepatic microsomal cytochrome P-450 (P-450) from C57BL/6 (B6) and DBA/2 (D2) inbred strains of mice, uninduced and treated with phenobarbital (PB), pregnenolone-16 alpha-carbonitrile (PCN), and beta-naphthoflavone (BNF), were assessed. The assessment was based on comparisons of the regioselectivity and stereoselectivity of warfarin metabolism, inhibition of metabolism by antibodies raised against highly purified rat P-450 isozymes (the specificity of these antibodies in inhibiting rat microsomal metabolism of warfarin was also determined), and by immunoelectrophoresis using the anti-(rat P-450). Isozymes were considered to be the same or very similar if they exhibited the same substrate specificity, antigenicity, and molecular weight. Untreated D2 and B6 mice had similar compositions of P-450 isozymes which were independent of the Ah receptor. Both strains contained an isozyme very similar to rat P- 450UT -A. PB or PCN induction of the two mouse strains proceeded independently of the Ah receptor and yielded isozymes which are the same as or very similar to the rat P- 450UT -A, P- 450PB -B, P- 450PB -C, and P- 450PB /PCN-E isozymes. D2 and B6 mice had similar isozyme compositions when treated with PB or PCN, but isozyme compositions varied in differently induced mice. BNF treatment of the D2 mice was without effect, but the B6 mice produced an isozyme(s) which was different from rat P- 450BNF -B, the major BNF-induced isozyme in rat liver.

Animals↗
PubMed1984

Correlations between polychlorinated biphenyl immunotoxicity, the aromatic hydrocarbon locus, and liver microsomal enzyme induction in C57BL/6 and DBA/2 mice.

The suppression of the antibody response by polychlorinated biphenyls (PCB) in mice is dependent on the planarity of the PCB molecule and on the expression of the aromatic hydrocarbon (Ah) receptor. In this study, the hypothesis that this form of immunotoxicity is a consequence of the activation of the Ah gene complex and that other compounds which are Ah receptor ligands would also be immunotoxic was tested. 2,2',4,4'-Tetrachlorobiphenyl (TCB), 2,3,3',4,4',5-hexachlorobiphenyl (HCB), phenobarbital (PB), or beta-naphthoflavone (BNF) was given ip to either C57BL/6 (B6,Ahb/Ahb) or DBA/2 (D2, Ahd/Ahd) mice 2 days before immunization with sheep erythrocytes. Organ weights, histopathology, hemagglutinating antibody titers, and the splenic direct antibody plaque-forming cell (PFC) response were evaluated on Day 5. Hepatic aryl hydrocarbon hydroxylase (AHH) induction by these compounds and by 2,2',5,5'-TCB and 3,3',4,4'-TCB was measured as an indicator of Ah receptor binding and subsequent activation of the Ah gene complex by methylcholanthrene-type inducers, while aminopyrine N-demethylase (APND) was measured as an indicator of PB-type induction. 2,2',4,4'-TCB and PB had no effects on the immune parameters of either strain but induced APND activity in both strains. 2,2',5,5'-TCB slightly induced APND activity in B6 mice. 2,3,3',4,4',5-HCB caused a 70% suppression of PFC per spleen, decreased the serum antibody titer, elevated cytochrome P-450 levels (193%), induced both APND (165%) and AHH (217%) activity in B6 mice, but it induced only APND (156%) activity in D2 mice. 3,3',4,4'-TCB elevated cytochrome P-450 levels (210%) and induced both APND (129%) and AHH (321%) activities in B6 mice but only increased APND activities (115%) in D2 mice. BNF elevated cytochrome P-450 (144%), caused a 49% suppression in PFC per spleen, and induced both APND (156%) and AHH (248%) activities but only in B6 mice. These results support the hypothesis that the immunotoxicity caused by halogenated and polycyclic aromatic hydrocarbons is a consequence of activation of the Ah gene complex and suggests that this toxic effect can be initiated by any Ah receptor ligand.

Aminopyrine N-Demethylase↗
PubMed1984

Subchronic exposure of mice to Love Canal soil contaminants.

The health hazard potential of soil collected from the surface of the Love Canal chemical dump site in Niagara Falls, New York, was assessed in 90-day exposure studies. Female CD-1 mice were exposed to two concentrations of the volatile components of 1 kg of soil with and without direct soil contact. Control mice were identically housed but without soil. The soil was replaced weekly and 87 compounds were detected in the air in the cages above fresh and 7-day-old soil as analyzed by gas chromatography/mass spectrometry. The concentration of many of these compounds decreased during the 7-day exposure cycle. Histopathologic, hematologic, and serum enzyme studies followed necropsy of all mice. There was no mortality of mice exposed for up to 90 days under any condition. Thymus and spleen weights relative to body weight were increased after 4 weeks of exposure by inhalation but not after 8 or 12 weeks of exposure. alpha-, beta-, and delta- Benzenehexachlorides , pentachlorobenzene, and hexachlorobenzene were detected in liver tissue from these animals. Mice exposed to 5- to 10-fold elevated concentration of volatiles had increased body and relative kidney weights. There was no chemically induced lesion in any animal exposed only to the volatile soil contaminants. Mice exposed by direct contact with the soil without elevated volatile exposure had increased body (10%) and relative liver weights (169%). Centrolobular hepatocyte hypertrophy, which involved 40 to 70% of the lobules, was observed in all mice in this group.(ABSTRACT TRUNCATED AT 250 WORDS)

Air↗