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Biomedical subjects

R E Kouri

Publications and source records attributed to R E Kouri.

At least 37 records · Page 2Linked to original sources
PubMed1984

Xeroderma pigmentosum fibroblasts are more sensitive to asbestos fibers than are normal human fibroblasts.

Xeroderma pigmentosum fibroblasts (XPF) are defective in the repair of certain DNA adducts. We show here that XPF cells are more sensitive to the toxic effects of chrysotile, amosite and crocidolite asbestos than are normal human fibroblasts (NF). XPF cells from different complementation groups have a sensitivity to chrysotile which parallels the degree of their DNA repair deficiency. In addition, the survival of normal cells after chrysotile exposure increases with time if they are kept from replicating, while the survival of XPF cells under the same circumstances does not change.

Asbestos↗
PubMed1984

Variations in aryl hydrocarbon hydroxylase activities in mitogen-activated human and nonhuman primate lymphocytes.

A fluorometric assay for the cytochrome P-450-dependent enzyme system, aryl hydrocarbon hydroxylase (AHH), was performed in mitogen-activated human lymphocytes from over 300 different humans and from 64 baboons. Results reveal: a) an average interindividual variation in AHH activity of approximately 0.25 (coefficient of variation); range of activities among humans and baboon subjects of approximately 40-fold; c) both genetic and environmental determinants of interindividual variation, and d) high AHH activity in humans associated with primary lung cancer. Confirmation of these results awaits the development of improved methods for phenotyping humans and for prospective cancer patient studies. DNA probes might be employed in future studies to determine specific mRNA content, and to search for DNA polymorphisms in and near the human cytochrome P-450 gene.

Animals↗
PubMed1984

Aryl hydrocarbon hydroxylase inducibility among primary relatives of children with leukemia or solid tumors.

In mice, there is a correlation between genetically regulated levels of inducible aryl hydrocarbon hydroxylase (AHH) activity and the risk of polycyclic hydrocarbon-induced leukemia or solid tumors. Recent clinical studies suggest a relationship between high AHH activity and lung cancer associated with cigarette smoking (Kouri, R.E., McKinney, C.E., Slomiany, D.J., Snodgrass, D.R., Wray, N.P., and McLemore, T.L. Cancer Res. 42: 5030-5037, 1982). To determine whether there is a similar genetic relationship in humans between inducible AHH and the occurrence of pediatric cancers, we examined AHH activity in mitogen-stimulated benzo(a)anthracene-treated lymphocyte cultures from primary relatives of children with leukemia or solid tumors. Control families (parents and siblings with no history of cancer) comprised friends or neighbors of the proband families. By comparing variance among family members with variance among nonrelated individuals, we conclude that a small, but real, genetic component is detectable. Adjusting for age, smoking history, and the length of time during which the lymphocytes had been cryopreserved, however, we find no difference among 77 leukemia, 71 solid tumor, and 100 control family members with regard to median units (+/- median S.E.) of maximally induced AHH activity per unit of reduced nicotinamide adenine dinucleotide-cytochrome c reductase activity: 0.31 +/- 0.03; 0.28 +/- 0.03; and 0.28 +/- 0.03, respectively. Thus, benzo(a)anthracene-induced AHH activity in cultured mitogen-activated lymphocytes in our study population does not appear to be associated with the risk of occurrence of childhood leukemia or solid tumors.

Aryl Hydrocarbon Hydroxylases↗
PubMed1983

Association between susceptibility to dibenzanthracene-induced fibrosarcoma formation and the Ah locus.

The relationship between the Ah locus and the induction of subcutaneous fibrosarcomas by dibenz[a,h]anthracene and dibenz[a,c]anthracene was investigated in C57BL/6J (Ahb/Ahb), (C57BL/6J)(DBA/2J)F1 (Ahb/Ahd) and (Ahd/Ahd) mice. Ahb/Ahb and Ahb/Ahd mice have the high-affinity Ah receptor and therefore the polycyclic hydrocarbon induction of aryl hydrocarbon hydroxylase activity (cytochrome P1-450) proceeds with ease; Ahd/Ahd mice have the poor-affinity Ah receptor and this induction process proceeds more poorly, by a factor of at least 10-fold. Dibenz[a,c]anthracene proved to be a relatively weak carcinogen, producing less than 3% tumor incidence at doses up to 300 micrograms per mouse. In contrast, dibenz[a,h]anthracene caused an almost 50% tumor incidence in Ahb/Ahb and Ahb/Ahd mice, while causing approximately 2% tumor incidence in Ahd/Ahd mice. Both isomers bind avidly to the cytosolic Ah receptor, and both chemicals induce aryl hydrocarbon hydroxylase activity in Ahb/Ahb and Ahd/Ahd animals. Among progeny of the (C57BL/6J) (DBA/2J) F1 X DBA/2J backcross, 63 of 100 Ahb/Ahd mice and none of 75 Ahd/Ahd mice developed tumors. These data demonstrate a strict correlation between susceptibility to dibenz[a,h]anthracene-induced subcutaneous tumors and expression of the Ahb allele, i.e. presence of the high-affinity Ah receptor and therefore readily inducible P1-450.

Alleles↗
PubMed1983

Biological effects of the Sudan dyes. Role of the Ah cytosolic receptor.

The hepatic induction of two cytochrome P1-450-mediated activities [aryl hydrocarbon hydroxylase (AHH) and ethoxyresorufin O-deethylase (ETR)] was studied following the administration of the azo dyes Sudan I, II, III, and IV. When using Ah-responsive C57BL/6J mice, Sudan dye II proved to be quite potent as an inducer causing almost maximal induction at doses as low as 40 mg/kg (1.4 mumoles/kg body weight); Sudan dyes I, III and IV caused one-half the maximal induction at four times that dose. In contrast, none of these compounds caused induction of AHH or ETR in the Ah-nonresponsive DBA/2J animals. When the dyes were given to B6D2F1 X D2 backcross progeny, a strict correlation with the presence of the Ahb allele and the inducibility of AHH and ETR was observed. When these compounds were examined as agonists for the Ah cytosolic receptor by their capacity to replace [3H]2,3,7,8-tetrachlorodibenzo-p-dioxin binding, Sudan dye II was substantially more effective than Sudan dyes I, III and IV. When four repeated doses of Sudan dye II were administered intraperitoneally to Ah-responsive C57BL/6J mice and Ah-nonresponsive DBA/2J mice, Sudan dye II-induced immunotoxicity was markedly greater in C57BL/6J compared to DBA/2J mice.

Animals↗
PubMed1983

Dibenz[a,h]anthracene-induced subcutaneous tumors in mice. Strain sensitivity and the role of carcinogen metabolism.

Four inbred strains of mice (C3H/HeJ, C57BL/6J, AKR/J, and DBA/2J) were injected s.c. with 150 micrograms of dibenz[a,h]anthracene and followed for 9 months. Strains C3H/HeJ and C57BL/6J were most susceptible to dibenz[a,h]anthracene-induced carcinogenesis with 80% and 53% incidence of tumors, respectively. Strains AKR/J and DBA/2J were much less sensitive with only one tumor observed out of a total of 60 treated mice. Dibenz[a,h]anthracene was shown to induce hepatic aryl hydrocarbon hydroxylase activity in the two sensitive strains, C3H/HeJ and C57BL/6J, but not in the two resistant strains, AKR/J and DBA/2J. When 3-methylcholanthrene-treated liver microsomes from the four strains were studied for dibenz[a,h]anthracene metabolism in vitro, the two sensitive strains not only demonstrated a 3- to 4-fold greater overall rate of metabolism than the two resistant strains, but also showed a quantitative shift with a greater percentage of the total metabolites being the 3,4-diol of dibenz[a,h]anthracene. This diol is the presumed precursor to the apparent ultimate carcinogen, dibenz[a,h]anthracene 3,4-diol-1,2-epoxide.

Animals↗
PubMed1983

Genetics of xenotropic virus expression in mice. II. Expression of major virus structural proteins in crosses involving NZB/B1NJ, SWR/J, and 129/J strains of mice.

The expression of viral structural polypeptides and the production of infectious xenotropic virus were found to segregate together in NZB, 129/J, and SWR/J mice and in crosses between these strains. The viral p30 protein segregation pattern, as measured by competition radioimmunoassay using extracts of frozen spleens from backcross progeny, indicate that xenotropic murine leukemia virus expression is controlled by two dominant genes.

Animals↗
PubMed1983

Induction of neoplastic transformation and DNA single-strand breaks in C3H/10T1/2 clone 8 cells by polycyclic hydrocarbons and alkylating agents.

The standard C3H/10T1/2 clone 8 (C3H/10T1/2 CL8) cell transformation assay was tested for its ability to identify a variety of polycyclic hydrocarbons and alkylating agents. Dose-dependent morphologic transformation occurred with benzo[a]pyrene (BaP), 3-methylcholanthrene (MCA), 7,12-dimethylbenz[a]anthracene, BaP-7,8-dihydroxy-7,8-dihydrodiol (BaP-7,8-diol), as well as with the relatively weak in vivo carcinogen benzo[e]pyrene. Dibenz[a,h]anthracene yielded a relatively weak response, whereas anthracene and phenanthrene were negative. In contrast, treatment of C3H/10T1/2 CL8 cells with two directly acting alkylating agents, N-nitroso-N-methylnitroguanidine (MNNG) and styrene oxide, gave no transformation, whereas a third alkylating agent, ethyl methanesulfonate (EMS), gave a weak response. Treatment with MCA (2.5 micrograms/ml) yielded a reproducible positive response and, therefore, served as a positive control for routine use of the C3H/10T1/2 CL8 assay. When cells treated with the hydrocarbons BaP, BaP-7,8-diol, or MCA were analyzed for nonspecific DNA damage (single-strand breaks or alkaline-labile sites) by alkaline elution techniques, little if any DNA damage was observed. In contrast, the alkylating agents MNNG, styrene oxide, and EMS yielded substantial numbers of single-strand breaks.

Alkylating Agents↗
PubMed1982

Positive correlation between high aryl hydrocarbon hydroxylase activity and primary lung cancer as analyzed in cryopreserved lymphocytes.

Blood samples from closely monitored patients at the Veterans Administration Hospital in Houston, Texas, were collected, coded, and sent to Microbiological Associates over an 8-month period. Lymphocytes were isolated and cryopreserved at -190 degrees. Lymphocyte samples were simultaneously thawed, phytohemagglutinin activated, and analyzed for benz(a)anthracene-induced aryl hydrocarbon hydroxylase (AHH) levels, [3H]thymidine incorporation, and reduced nicotinamide adenine dinucleotide-dependent cytochrome b5 (cytochrome c) reductase activity. Determinations were made at both 96 and 120 hr in culture, and peak activities were compared among a total of 51 individuals who expressed such lesions as squamous cell carcinomas (22%), adenocarcinomas (14%), oat cell carcinomas (6%), chronic obstructive pulmonary disease (22%), and other nonmalignant diseases. Of the 14 highest AHH/cytochrome c activities observed, all were found in patients with primary lung cancer. Mean AHH/cytochrome c activities were 0.89 for lung cancer patients (a total of 21) and 0.47 for noncancer patients (a total of 30) (p less than 0.001). No relationship was observed between AHH/cytochrome c activity and age of patient, numbers of cigarettes smoked, family history of cancer, location or histological type of tumor, or level of phytohemagglutinin blastogenesis ([3H]thymidine cpm/cytochrome c). Whether the higher AHH levels are the cause or the result of the primary lung cancer remains to be determined.

Adult↗
PubMed1981

A method for detecting aryl hydrocarbon hydroxylase activities in cryopreserved human lymphocytes.

Aryl hydrocarbon hydroxylase (AHH) activity, NADH-dependent cytochrome c reductase (cyt c) activity, and [3H]thymidine (3H-TdR) incorporation were monitored in human lymphocytes cryopreserved for periods up to 1 year. A standard procedure for freezing, thawing and culturing of these lymphocytes was developed. Kinetics for expression of benz[a]anthracene-(BA)-induced AHH activity, cyt c activity, and 3H-TdR incorporation were similar in both freshly cultured and cryopreserved cells. Lymphocyte samples from 10 individuals were collected once per month over a 3-month period and cells were either cultured at the time of donation or cryopreserved for later assay. Results indicated that the cryopreserved lymphocytes efficiently responded to mitogen activation. The intra-individual variation in AHH activities was reduced in the cryopreserved lymphocytes compared to the freshly cultured cells, and the relative ranking of these individuals in terms of their AHH activities remained constant for both fresh and cryopreserved samples. Cryopreservation seems to offer significant advantages over the freshly cultured lymphocytes because it allows for lymphocyte samples to be collected in diverse geological locations and over extended periods of time and yet permits for the culture and assay of all the cell samples at exactly the same time.

Aryl Hydrocarbon Hydroxylases↗
PubMed1981

DNA replication and unscheduled DNA synthesis in lungs of mice exposed to cigarette smoke.

Mice of the hybrid strain BC3F1/Cum (C57BL/Cum X C3H/AnfCum) were chronically exposed to measured amounts of machine-generated whole Kentucky reference 2A1 cigarette smoke. DNA replication and unscheduled DNA synthesis (UDS) were measured in lung tissue in vitro using a short-term organ culture method. Within one week of beginning smoke exposure, DNA replicative activity, as indicated by incorporation of [3H]-thymidine into total lung DNA, was increased more than two-fold over sham-exposed controls and remained elevated as long as smoke exposure was continued. Treatment of lung tissues in vitro with either the lung carcinogen 4-nitroquinoline-1-oxide or methylmethane sulfonate stimulated UDS, measured as incorporation of [3H]thymidine into lung DNA in the presence of hydroxyurea, presumably as the result of DNA repair activity. Until the 10th to 12th week of smoke exposure, at which time the accumulated deposition of total particulate material in the lung was approximately 40 mg, the level of UDS stimulated by the alkylating chemicals declined to approximately 50% of that seen in lung tissue from sham-exposed control mice. If the mice were removed from smoke exposure, DNA replicative activity returned to normal levels within one week, but the UDS response to DNA damage remained depressed up to five months after ending smoke exposure. The results show that both transient and apparently permanent changes are produced in mouse lung as the result of exposure to cigarette smoke. The role of these changes in lung neoplasia is under investigation.

4-Nitroquinoline-1-oxide↗
PubMed1981

Lung cancer model system using 3-methylcholanthrene in inbred strains of mice.

A model system has been established for studying lung carcinogenesis using intratracheal instillation of 3-methylcholanthrene in C3H/AnfCum and C57BL/Cum X C3H/AnfCum F1 (hereafter called BC3F1/Cum) mice. The animals in these studies were screened for adventitious agents and were free throughout their lifetime of two important lung viruses, Sendai virus and pneumonia virus of mice. Under these conditions, the occurrence of spontaneous and chemically indiced lung cancers was determined over the lifetime of the animals. Data were analyzed by the actuarial method for lung tumor probability. Probability was found to be dose and time dependent. Over 95% of the 3-methylcholanthrene-treated BC3F1/Cum and over 88% of the C3H/AnfCum mice were found at death to have pulmonary carcinomas. Tumors observed in animals which died up to 40 weeks on test were almost always squamous cell carcinomas (approximately 85%), while tumors which were observed in animals which died after 50 weeks were mainly alveolar adenocarcinomas (approximately 80%). Both tumors types metastasized widely. Spontaneous lung cancers (only alveolar adenocarcinomas were observed) occurred in these two strains at low frequency and were expressed late in life. Thus, the system described affords a suitable model to study the induction, expression, and progression of lung tumors under conditions where a vast majority of animals develop neoplasia.

Animals↗
PubMed1980

Correlation of inducibility of aryl hydrocarbon hydroxylase with susceptibility to 3-methylcholanthrene-induced lung cancers.

C57BL/6Cum, DBA/2Cum, first filia (F1), and backcross progeny from these 2 parental strains of mice were evaluated for their susceptibility to 3-methylcholanthrene-induced lung cancers. In the crosses among these mice, aryl hydrocarbon hydroxylase (AHH) responsiveness segregated as a single autosomal dominant gene (the Ah locus). AHH responsive mice (Ahb allele) expressed 40-60 units AHH activity/g wet wt liver following intraperitoneal treatment with 3-methylcholanthrene (MCA) compared to AHH non-responsive mice (Ahd allele) which expressed 7-11 units AHH activity/g wet wt liver after MCA treatment. Intratracheal administration of 500 microgram MCA for a total of 4 times at weekly intervals yielded a variety of pulmonary cancers, including squamous cell carcinomas, alveolar adenocarcinomas, and adeno-squamous cell carcinomas among mice that survived 1 year after the carcinogen treatment. The AHH responsive C57BL/6Cum, F1, and C57BL/6Cum X F1 animals were much more susceptible to MCA-induced lung cancers than the AHH non-responsive DBA/2Cum mice. The lung cancers were also not randomly distributed in DBA/2Cum X F1 backcross progeny since significantly more lung cancers were found in AHH-responsive progeny than in AHH non-responsive mice. Data support genetic linkage between susceptibility to MCA-induced lung carcinomas and the Ahb allele.

Animals↗
PubMed1980

Xenotropic virus expression and susceptibility to 3-methylcholanthrene-induced cancer.

This paper reports the lack of genetic linkage between spontaneous production of substantial amounts of infectious xenotropic (X-tropic) virus and the susceptibility to chemically induced cancers in two inbred strains of mice, NZB/BLNJ and 129/J, and their genetic crosses. The parental strains and F1, backcross, and F2 progeny between these two strains were partially splenectomized to ascertain X-tropic viral status and were subsequently treated s.c. with 500 microgram of 3-methylcholanthrene in trioctanoin. Progeny from second backcrosses [(F1 X 129) X 129] were also tested for their X-tropic viral status and susceptibility to 3-methylcholanthrene carcinogenesis. Mice were observed for evidence of fibrosarcomas at the site of inoculation over a 10-month period. In this genetic system, spontaneous production of high titers of X-tropic virus segregated as a single autosomal dominant gene. Susceptibility to 3-methylcholanthrene-induced fibrosarcomas did not segregate in these crosses, and susceptibility did not correlate with the degree of X-tropic virus expression.

Animals↗
PubMed1979

C-type RNA virus from hamster cells transformed in vitro by 1-B-D-arabinofuranosylcytosine.

Evidence of type-C RNA viral activity in fetal hamster cells transformed in vitro by 1-B-D-arabinofuranosylcytosine (ara-C) after at least one in vivo passage is described. The virus possesses properties typical of other type-C RNA viruses, such as: a) morphology as determined with the electron microscope, b) presence of 70S RNA, c) enhanced expression following treatment with halogenated pyrimidines, d) group specific antigens of hamster type, and e) a buoyant density of 1.15 g per cm3. However, the virus particles are deficient in RNA-dependent DNA polymerase activity under conditions that easily detect Rauscher Leukemia virus and will infect neither hamster, rat, mouse, human nor rabbit cells. The possible role of this virus in chemical carcinogenesis of cultured hamster fetal cells is discussed.

Animals↗