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C D Davis

Publications and source records attributed to C D Davis.

At least 55 records · Page 3Linked to original sources
PubMed1994

Cardiotoxicity of heterocyclic amine food mutagens in cultured myocytes and in rats.

Cooked meat contains a number of mutagenic/carcinogenic heterocyclic amines, including 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]-pyridine (PhIP). We recently observed that monkeys treated with IQ showed myocyte degeneration and mitochondrial changes. Thus, it was of interest to develop models to investigate heterocyclic amine cardiotoxicity. Primary cultures of fetal rat myocytes were exposed to the activated forms of the carcinogens (N-OH-IQ and N-OH-PhIP). LDH leakage increased in proportion to the carcinogen dose but was significantly greater in cells exposed to N-OH-IQ than that in cells exposed to N-OH-PhIP. Electron microscopy revealed that treated cells had swollen and irregular mitochondria and fewer organelles. However, DNA adducts, assessed using the 32P-postlabeling method, were significantly higher in myocytes exposed to N-OH-PhIP than in cells exposed to N-OH-IQ. The toxic effects of heterocyclic amines were also evaluated in rats given IQ or PhIP (100 mg/kg, po 10 doses over 2 weeks). Light microscopic and ultrastructural cardiac abnormalities were present in seven of eight rats exposed to IQ or PhIP. Whereas control animals had a normal cardiac morphology, carcinogen-treated animals had foci of chronic inflammation with myocyte necrosis, myofibrillar dissolution and disarray, and dilation of T-tubules. These results suggest that, in addition to being carcinogenic, food mutagens may play a role in cardiac degeneration.

Animals↗
PubMed1994

Sorting signals in the MHC class II invariant chain cytoplasmic tail and transmembrane region determine trafficking to an endocytic processing compartment.

Targeting of MHC class II molecules to the endocytic compartment where they encounter processed antigen is determined by the invariant chain (Ii). By analysis of Ii-transferrin receptor (TR) chimera trafficking, we have identified sorting signals in the Ii cytoplasmic tail and transmembrane region that mediate this process. Two non-tyrosine-based sorting signals in the Ii cytoplasmic tail were identified that mediate localization to plasma membrane clathrin-coated pits and promote rapid endocytosis. Leu7 and Ile8 were required for the activity of the signal most distal to the cell membrane whereas Pro15 Met16 Leu17 were important for the membrane-proximal signal. The same or overlapping non-tyrosine-based sorting signals are essential for delivery of Ii-TR chimeras, either by an intracellular route or via the plasma membrane, to an endocytic compartment where they are rapidly degraded. The Ii transmembrane region is also required for efficient delivery to this endocytic processing compartment and contains a signal distinct from the Ii cytoplasmic tail. More than 80% of the Ii-TR chimera containing the Ii cytoplasmic tail and transmembrane region is delivered directly to the endocytic pathway by an intracellular route, implying that the Ii sorting signals are efficiently recognized by sorting machinery located in the trans-Golgi.

Amino Acid Sequence↗
PubMed1994

Adduction of the heterocyclic amine food mutagens IQ and PhIP to mitochondrial and nuclear DNA in the liver of Fischer-344 rats.

The heterocyclic amines 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) are carcinogens that form DNA adducts. In the present study, we used the 32P-postlabeling method to measure the levels of IQ and PhIP adducts in hepatic nuclear and mitochondrial DNA of Fischer-344 rats given a single dose (100 mg/kg, p.o.) or 10 doses of either carcinogen. After a single dose of IQ, adduct levels were > 2-fold higher in hepatic nuclear than in mitochondrial DNA; however, after repeated IQ exposure, the levels of adducts in nuclear and mitochondrial DNA were not significantly different. In contrast, after a single dose of PhIP, there were no significant differences in adduct levels in nuclear and mitochondrial DNA; however, after multiple doses of PhIP, adduct levels were significantly higher in mitochondrial DNA than in nuclear DNA. The percentages of individual IQ or PhIP adducts were different between nuclear DNA and mitochondrial DNA, particularly after 10 doses. With IQ, the C8-guanine adduct accounted for 72% of the total IQ adduct levels in nuclear DNA but only 40% of total adduct levels in mitochondrial DNA. After 10 doses of PhIP, the C8-guanine adduct accounted for 48% and 15% of total adduct levels in nuclear DNA and mitochondrial DNA respectively. In addition, the percentage of an uncharacterized PhIP adduct was 14% in nuclear DNA but < 1% in mitochondrial DNA. The percentages of individual adducts were approximately the same 3, 24, 120 and 240 h after a single dose of either compound, though total IQ and PhIP adduct levels appeared to decline over time in both organelles. The significance of IQ and PhIP mitochondrial DNA adduction and the influence of distinct heterocyclic amine adducts on carcinogenesis merit further investigation.

Animals↗
PubMed1993

Studies on the mutagenic activation of heterocyclic amines by cynomolgus monkey, rat and human microsomes show that cynomolgus monkeys have a low capacity to N-oxidize the quinoxaline-type heterocyclic amines.

A number of mutagens and carcinogens have been isolated from cooked meats. In the current study we investigated the ability of hepatic microsomes from cynomolgus monkeys, Fischer-344 rats and humans to metabolically activate these compounds. Monkeys had almost no capacity to activate the quinoxaline-type compounds to mutagens in the Ames test relative to rats and humans but were able to activate the quinoline, pyridoindole and pyridoimidazole compounds. Differences in the mutagenicity of the quinoline and quinoxaline compounds by monkeys and rats was related to differences in cytochrome P-450-mediated N-oxidation between the species. This suggests that monkeys and rats may have different hepatic cytochrome P-450 isozymes, which are important for the metabolic activation of quinolines and quinoxalines, or that the orthologous monkey cytochromes show a select substrate specificity for the quinolines over the quinoxalines.

Animals↗
PubMed1993

Mutagenic activation of IQ, PhIP and MeIQx by hepatic microsomes from rat, monkey and man: low mutagenic activation of MeIQx in cynomolgus monkeys in vitro reflects low DNA adduct levels in vivo.

Cooked meat, poultry and fish contain a number of mutagenic and carcinogenic heterocyclic amines, including 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). In the present study we examined the capacity of hepatic microsomes from Fischer 344 rats, cynomolgus monkeys and humans to metabolically activate IQ, MeIQx and PhIP in vitro using the Ames Salmonella mutagenicity assay. The mutagenic activation of IQ was similar among the three species; however, there were significant differences among the species in the activation of PhIP and MeIQx. Liver microsomes from humans showed the greatest capacity to activate PhIP and MeIQx, followed by rats, and then monkeys. The largest differences between the species were observed when MeIQx was used as the mutagen. MeIQx-DNA adducts formed in vivo were then compared among rats and monkeys given MeIQx by gavage (20 mg/kg/day, 10 doses). 32P-Postlabeling analysis, carried out under intensification conditions, was used to examine MeIQx-DNA adducts in the liver, kidney, heart, colon and white blood cells. MeIQx-DNA adducts were highest in all tissues examined from male rats, followed by female rats, and much lower in monkeys. In the liver, the total MeIQx-DNA adduct levels of monkeys were approximately 19 and approximately 10 times lower than in male and female rats respectively. In extrahepatic tissues, the differences in MeIQx-DNA adduct levels between monkeys and rats were even greater. The results suggest that the low level of MeIQx-DNA adducts found in vivo in cynomolgus monkeys reflects a low capacity to activate MeIQx via the hepatic cytochrome P450 monooxygenase system.

Animals↗
PubMed1993

Enzymatic phase II activation of the N-hydroxylamines of IQ, MeIQx and PhIP by various organs of monkeys and rats.

2-Amino-3-methylimidazo[4,5-f]quinoline (IQ), 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) are mutagenic and carcinogenic heterocyclic amines produced during the ordinary cooking of meat. These compounds undergo metabolic activation via both cytochrome P450-mediated N-oxidation and phase II esterification in order to exert their genotoxicity. In the current study, we examined the in vitro phase II activation of N-hydroxy-IQ, N-hydroxy-PhIP and N-hydroxy-MeIQx by cytosolic acetyltransferase, sulfotransferase, aminoacyl-tRNA synthetase and phosphatase from a number of tissues including liver, kidney, colon and heart. These tissues were chosen for study because each is either a target organ for carcinogenicity or has displayed high levels of DNA adducts in in vivo studies with the heterocyclic amines. Cytosol from various tissues of both monkeys and rats was incubated with and without the respective cofactors, and carcinogen binding to calf thymus DNA was measured by 32P-postlabeling analysis. Our results show that all four phase II enzymes may participate in the activation of the N-hydroxylamines. However, the degree of activation depends on the substrate, tissue and animal species. For example, in both monkeys and rats, the highest acetyl CoA-enhanced binding was observed with N-hydroxy-IQ and the lowest acetyl CoA-enhanced binding was observed with N-hydroxy-MeIQx. In contrast, no significant adenosine 3'-phosphate 5'-phosphosulfate-dependent activation of N-hydroxy-IQ was observed with monkey cytosol from liver, kidney, heart or colon but the sulfotransferase-mediated activation of N-hydroxy-PhIP was at least 10 times higher in all four tissues of monkeys than in rats. Prolylation appears important in the activation of all three N-hydroxylamines by rat liver and heart cytosol, whereas in monkeys, prolylation appears important in kidney cytosol. The differences observed in the phase II activation of heterocyclic amines may have implications for DNA adduct formation, toxicity and carcinogenicity.

Acetyltransferases↗
PubMed1993

32P-postlabeling analysis of IQ, MeIQx and PhIP adducts formed in vitro in DNA and polynucleotides and found in vivo in hepatic DNA from IQ-, MeIQx- and PhIP-treated monkeys.

The 32P-postlabeling method was used to examine the adducts in DNA, polynucleotides, and mononucleotides reacted in vitro with the N-hydroxy and N-acetoxy derivatives of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), 2-amino-3, 8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) or 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). Adduct profiles were compared to those found in vivo in liver of cynomolgus monkeys fed IQ, MeIQx or PhIP. The N-acetoxy derivatives of IQ, MeIQx and PhIP (generated in situ from the corresponding N-hydroxylamine in the presence of acetic anhydride) each formed three principal adducts in DNA. Adduct 1 of IQ, MeIQx and PhIP was chromatographically identical to the 32P-labeled bis(phosphate) derivative of N-(deoxyguanosin-8-yl)-IQ, N-(deoxyguanosin-8-yl)-MeIQx, and N-(deoxyguanosin-8-yl)-PhIP respectively, and this adduct comprised approximately 65% of total adduct levels found in DNA in vitro. The C8-guanine adduct and the two minor adducts were also found in poly(dG-dC). poly(dG-dC), suggesting that the two minor adducts of IQ, MeIQx and PhIP are also formed on the guanine base. The N-acetoxy derivatives of IQ, MeIQx, and to a much lesser extent PhIP, also formed adducts with adenine-containing polynucleotides including poly(dA), poly(dA).poly(dT) and poly(dA-dT).poly(dA-dT), but these adenine adducts were chromatographically different from those found in DNA. The three guanine adducts of N-acetoxy-IQ, -MeIQx and -PhIP found in vitro in DNA and in guanine-containing polynucleotides were also found in the liver of monkeys fed IQ, MeIQx or PhIP respectively, indicating that metabolic activation via N-hydroxylation and esterification occurred in vivo in monkeys. With each compound, the C8-guanine adduct was the predominant adduct found in vivo. The results indicate similarities among IQ, MeIQx and PhIP in the DNA adducts formed in vitro and in vivo and substantiate the use of the 32P-postlabeling method for comparative adduct studies.

Animals↗
PubMed1993

Empirical selection of psychosocial treatment targets for children and adolescents with diabetes.

Used an empirical approach to determine psychosocial variables related to optimal metabolic control of diabetes in two samples (total n = 56) of children and their families. Children and adolescents classified as either in optimal or nonoptimal control of diabetes (based on glycosylated hemoglobin results) completed self-report measures on variables of anxiety, coping, family environment and health locus of control, and a structured interview. Parents completed parallel self-report measures and a child behavior checklist. Children in optimal control of diabetes had more structured and controlling family environments, and more frequently believed that "powerful others" were responsible for their health. There was a marginally significant difference in knowledge, with children in poorer metabolic control showing better knowledge about diabetes and its management than children in optimal control. The study illustrates an empirical approach to the selection of psychosocial treatment targets for children with diabetes, and underscores the importance of parental involvement with the diabetes regimen to ensure optimal control of diabetes in both children and adolescents.

Adaptation, Psychological↗
PubMed1993

Manganese metabolism in rats: an improved methodology for assessing gut endogenous losses.

Manganese homeostasis is believed to be maintained by excretion of excess absorbed manganese through the gut, but the extent of endogenous gut losses of manganese has not been quantitated. We developed a model with rats to quantitate endogenous gut losses of manganese in which the parenterally administered isotope was distributed like fed isotope. Intraportally injected 54Mn complexed to albumin distributed in tissues like the fed isotope, but carrier-free 54Mn injected intraperitoneally, intravenously, or intraportally, or 54Mn complexed to transferrin and injected intraportally did not. Thus, manganese appears to be complexed to albumin or an albumin-like protein when it leaves the intestine. A mathematical model of manganese metabolism in rats fed 54Mn was developed using the SAAM and CONSAM computer programs. It was determined that the liver, not the pancreas, was the major source of endogenous gut losses of manganese. Young, growing rats fed 45 micrograms of Mn/g diet were calculated to absorb 8.2% of their manganese intake and then to lose 37% of the absorbed manganese through gut endogenous losses.

Animals↗
PubMed1992

Longitudinal changes of manganese-dependent superoxide dismutase and other indexes of manganese and iron status in women.

The effect of dietary factors on manganese-dependent superoxide dismutase (MnSOD) activity in humans has not been studied. We longitudinally evaluated changes in MnSOD activity and other indices of manganese and iron status in 47 women during a 124-d supplementation study. Subjects received one of four treatments: placebo, 60 mg iron, 15 mg manganese, or both mineral supplements daily. Manganese supplementation resulted in significant increases in lymphocyte MnSOD activity and serum manganese concentrations from baseline values but no changes in urinary manganese excretion or in any indices of iron status. Oral contraceptive use and the stage of the menstrual cycle did not confound the use of lymphocyte MnSOD activity or serum manganese to monitor manganese status, but fat intake affected both indices. This work demonstrated that lymphocyte MnSOD activity can be used with serum manganese concentrations to monitor manganese exposure in humans.

Adult↗
PubMed1992

Interactions among dietary manganese, heme iron, and nonheme iron in women.

The relationship among dietary intake of heme iron, nonheme iron, and manganese on indexes of hematological and nutritional status in regard to manganese of 47 women consuming their typical diets was investigated. Increasing dietary iron intake, by consuming more nonheme iron in the diet, had questionable effects on hematological status (hematocrit values and ferritin and transferrin concentrations) and negative effects on nutritional status in regard to manganese (serum manganese, urine manganese, and lymphocyte manganese-dependent superoxide dismutase activity). In contrast, heme-iron intake was positively correlated with hematological status and had no consistent effect on nutritional status in regard to manganese. Differences in dietary manganese intake had no consistent effect on indices of manganese or iron status, possibly because foods that contain significant amounts of manganese (green vegetables, breads, and cereals) often contain significant amounts of nonheme iron. Thus, increasing dietary manganese intake by consuming these foods is apt to have limited impact on manganese status because of the interaction between nonheme iron and manganese.

Diet↗
PubMed1992

Varying levels of manganese and iron affect absorption and gut endogenous losses of manganese by rats.

The interactive effects of manganese and iron on true absorption and endogenous losses of manganese were investigated by feeding rats three levels of manganese (0.9, 48 or 188 micrograms Mn/g diet) and two levels of iron (19 or 276 micrograms Fe/g diet) for 7 wk. After 45 d, half of the rats were fed 54Mn and half were injected intraportally with 54Mn complexed to albumin. The relative distribution of 54Mn in tissues was generally similar for rats when 54Mn was administered in these two ways. Manganese-deficient animals retained more of the isotope, had both higher apparent and higher true absorption of manganese, had a greater proportion of 54Mn in their livers and had a lower proportion of 54Mn in their muscles compared with animals fed adequate or high levels of manganese. High iron intake inhibited manganese true absorption, reduced tissue manganese concentrations and inhibited heart manganese-dependent superoxide dismutase activity. However, the greatest effect of dietary iron was on mucosal cell manganese concentrations. Endogenous losses of manganese were approximately 8% of the amount of manganese actually absorbed regardless of intake. Thus, control of absorption in the gut seems to be the major way that manganese homeostasis is maintained. Furthermore, iron seems to be depressing manganese absorption by inhibiting manganese uptake into the mucosal cells.

Absorption↗
PubMed1992

Changes in humoral responses to Trypanosoma cruzi during the course of infection in mice held at elevated temperature.

A parasite-specific, enzyme-linked immunosorbent assay and immunoblot analysis were used to examine the development of humoral immunity in Trypanosoma cruzi-infected C3H mice that survive acute infection when held at elevated environmental temperature. Both parasite-specific antibody levels and numbers of antigens identified increased during infection in mice held at 36 C, with the greatest reactivity measured in sera from mice that had resolved parasitemias. Heat shock of culture forms of T. cruzi resulted in production of different antigens, but there was no strong difference in the antigens recognized by sera from mice held at room temperature and those recognized by sera from mice held at 36 C. Immunoblot analysis using blood-form trypomastigote antigens identified a band of approximately 61 kDa produced by trypomastigotes in mice held at 36 C that was strongly detected by sera from mice held at 36 C. Little if any reactivity to this antigen was observed using sera from mice held at room temperature.

Animals↗
PubMed1991

Effect of elevated environmental temperature on the antibody response of mice to Trypanosoma cruzi during the acute phase of infection.

When held at 36 degrees C, Trypanosoma cruzi-infected C3H mice survive an otherwise lethal infection with significantly decreased parasitemia levels and enhanced immune responsiveness. Treatment of T. cruzi-infected mice with the immunosuppressive agent cyclophosphamide indicated that the positive effects of increased environmental temperature were primarily due to enhancement of immunity. A parasite-specific, enzyme-linked immunosorbent assay and immunoblot analysis were used to examine the effect of elevated environmental temperature on the production of anti-T. cruzi antibodies. Both the reactivity and diversity of anti-T. cruzi antibodies were found to be lower in infected mice held at 36 degrees C than in infected mice held at room temperature. However, reactivity and diversity could be enhanced by vaccination with culture forms of the parasite.

Acute Disease↗