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Biomedical subjects

A D Mitchell

Publications and source records attributed to A D Mitchell.

At least 73 records · Page 4Linked to original sources
PubMed1983

Unscheduled DNA synthesis tests. A report of the U.S. Environmental Protection Agency Gene-Tox Program.

The utility of unscheduled DNA synthesis (UDS) testing for screening potentially hazardous chemicals was evaluated using the published papers and technical reports available to the UDS Work Group. A total of 244 documents were reviewed. Based on criteria defined in advance for evaluation of the results, 169 were rejected. From the 75 documents accepted, results were reviewed for 136 chemicals tested using autoradiographic approaches and for 147 chemicals tested using liquid scintillation counting (LSC) procedures; 38 chemicals were tested by both approaches to measure UDS. Since there were no documents available that provided detailed recommendations of UDS screening protocols or criteria for evaluating the results, the UDS Work Group presents suggested protocols and evaluation criteria suitable for measuring and evaluating UDS by autoradiography in primary rat hepatocytes and diploid human fibroblasts and by the LSC approach in diploid human fibroblasts. UDS detection is an appropriate system for inclusion in carcinogenicity and mutagenicity testing programs, because it measures the repair of DNA damage induced by many classes of chemicals over the entire mammalian genome. However, for this system to be utilized effectively, appropriate metabolic activation systems for autoradiographic measurements of UDS in human diploid fibroblasts must be developed, the nature of hepatocyte-to-hepatocyte variability in UDS responses must be determined, and the three suggested protocols must be thoroughly evaluated by using them to test a large number of coded chemicals of known in vivo mutagenicity and carcinogenicity.

Animals↗
PubMed1983

Immune response to hepatitis B vaccine in newborns.

Three injections of 10 microgram/ml hepatitis B vaccine (Merck) given in the first week after birth, a month later and again at the age of six months to 63 neonates in a rural African population, elicited an antibody response in 93 per cent. The initial hepatitis B marker status of the babies and mothers did not influence the results at nine months. Side-effects were minor and we conclude that the vaccine can effectively and safely be used from birth in endemic situations.

Female↗
PubMed1980

Evidence that physiologic levels of circulating estrogens and neonatal sex-imprinting modify postpubertal hepatic microsomal 3-hydroxy-3-methylglutaryl coenzyme A reductase activity.

Intact, but sham-operated female rats had 2- to 3-fold higher levels of hepatic 3-hydroxy-3-methylglutaryl CoA reductase activity than their male counterparts (15--21.5 vs. 6.7--8.7 nmol mevalonate/mg protein per h). The activity of the hepatic enzyme declined to about the same relative degree (40--60%) in male and female rats that were gonadectomized after puberty (53 days of age) and killed 5 weeks later. Implantation of silastic capsules containing 17 beta-estradiol increased the level of hepatic 3-hydroxy-3-methylglutaryl CoA reductase to levels found in sham-operated controls. In rats that were gonadectomized in infancy (12 h old) and killed 7--8 weeks later, the level of enzyme activity was not altered in females, but it was increased from 60--240% in males. Consequently, following neonatal gonadectomy, male-female differences in enzyme activity were no longer apparent. Implantation of silastic capsules containing estradiol in neonatally gonadectomized rats resulted in a doubling of enzyme activity in both males and females. Ovariectomy reduced plasma estrogen levels, but implantation of estradiol in gonadectomized males and females increased the hormone level to that found in sham-operated females. Thus, the results strongly suggest a role for physiologic levels of estrogen as a positive effector of 3-hydroxy-3-methylglutaryl CoA reductase activity. Neonatal sex imprinting also appears to modulate the enzyme activity since sex-mediated differences are effaced by gonadectomy in infancy, but not by gonadectomy following puberty.

Animals↗
PubMed1980

An overview of short-term tests for the mutagenic and carcinogenic potential of pesticides.

In the last few years, marked progress has been made in the development of methods for evaluating the mutagenic and carcinogenic potential of pesticide chemicals. The correlation of genetic and related biological activity in short-term tests with carcinogenic activity in whole animals allows the utilization of short-term mutagenicity bioassays to prescreen chemicals for effects related to mutation induction and presumptive carcinogenicity. In addition, bioassays now available can measure directly the chemical transformation of normal cells in culture into cells capable of producing tumors when injected into animals. This paper will review briefly the major types of relevant short-term tests and will develop a rationale for a phased approach to the evaluation of the mutagenic and carcinogenic potential of environmental chemicals. This approach involves the sequential application of bioassays which are organized into a three-level matrix emphasizing first detection, then confirmation, and finally hazard assessment. Chemicals demonstrating positive results in the short-term detection systems and confirmatory bioassays are pursued in higher level whole animal define a negative result. The phased approach should facilitate a cost effective utilization of limited testing resources and provide protection for human health in proportion to the anticipated hazard. Results obtained in evaluating a series of thirty-eight pesticide chemicals according to the phased approach discussed in detail.

Animals↗
PubMed1979

Mutagenicity tests of diflubenzuron in the micronucleus test in mice, the L5178Y mouse lymphoma forward mutation assay, and the Ames Salmonella reverse mutation test.

Diflubenzuron, one of a new class of pesticides believed to act via inhibition of chitin synthesis in the developing insect cuticle, was tested for possible mutagenic activity using the micronucleus test in mice, the L5178Y mouse lymphoma forward mutation test at the thymidine kinase locus, and the Ames Salmonella/microsome reverse mutation test. No mutagenic effect was found.

Animals↗
PubMed1978

Sex-related differences in diurnal activities and development of hepatic microsomal 3-hydroxy-3-methylglutaryl coenzyme A reductase and cholesterol 7alpha-hydroxylase.

The activities of hepatic microsomal 3-hydroxy-3-methylglutaryl CoA reductase and cholesterol 7alpha-hydroxylase were consistently higher (up to 3-fold) in female compared to male rats fed 2% cholestyramine for 8 h daily. In all animals studied, enzymic activities were highest 6 h after feeding began. However, 85% of the rise in cholesterol 7alpha-hydroxylase activity occurred in the 6 h before and 89% of the rise in 3-hydroxy-3-methylglutaryl CoA reductase activity occurred in the 6 h after feeding started. Sex-related differences in both enzymic activities first became apparent at the time of sexual maturity. Enzymic activities before weaning were generally low and a late-suckling (13--20 days) rise in cholesterol 7alpha-hydroxylase was not accompanied by a rise in 3-hydroxy-3-methylglutaryl CoA reductase. For all of these studies we assayed cholesterol 7alpha-hydroxylase at two concentrations of exogenous cholesterol to obviate problems relating to size of the cholesterol pool.

Aging↗
PubMed1978

Citreoviridin, a specific inhibitor of the mitochondiral adenosine triphosphatase.

1. Citreoviridin was a potent inhibitor of the soluble mitochondrial ATPase (adenosine triphosphatase) similar to the closely related aurovertins B and D. 2. Citreoviridin inhibited the following mitochondrial energy-linked reactions also: ADP-stimulated respiration in whole mitochondria from ox heart and rat liver; ATP-driven reduction of NAD+ by succinate; ATP-driven NAD transhydrogenase and ATPase from ox heart submitochondrial particles. 3. The dissociation constant (KD) calculated by a simple law-of-mass-action treatment for the citreoviridin--ATPase complex was 0.5--4.2micron for ox-heart mitochondrial preparations and 0.15micron for rat liver mitochondria. 4. Monoacetylation of citreoviridin decreased its inhibitory potency (KD=2--25micron, ox heart; KD=0.7micron, rat liver). Diacetylation greatly decreased the inhibitory potency (KD=60--215micron, ox heart). 5. Hydrogenation of citreoviridin monoacetate diminished its inhibitory potency considerably. 6. No significant enhancement of fluorescence was observed when citreoviridin interacted with the mitochondrial ATPase.

Acetates↗
PubMed1978

The role of transamination in methionine oxidation in the rat.

The role of transamination as the initial step in catabolism of methionine in the rat was investigated. [Methyl-14C] or [1-14C]-L-Methionine was added to tissue homogenates and transamination was determined from the counts recovered in a precipitable phenylhydrazone following treatment of the samples with 2,4-dinitrophenylhydrazine. Transamination of methionine was detected in homogenates of liver, kidney, heart, brain, spleen, skeletal muscle, and small intestines. The product of methionine transamination in the liver was identified as alpha-keto-gamma-methiolbutyrate. Approximately the same tissue distribution was observed for the conversion of the methyl or carboxyl carbon of methionine or alpha-keto-gamma-methiolbutyrate to CO2. alpha-Keto-butyrate could be used as a co-substrate for transamination, but inhibited oxidation of methionine apparently by competing for oxidation of alpha-keto-gamma-methiolbutyrate. S-Adenosyl-L-methionine was not a substrate for transamination in the liver homogenate system nor did it inhibit transamination of methionine. Amino-oxyacetic acid inhibited transamination and oxidation of methionine, but not oxidation of alpha-keto-gamma-methiolbutyrate. These observations are consistent with transamination being an initial step in methionine catabolism and an alternate pathway for methionine oxidation which does not involve its activation to S-adenosyl-L-methionine.

Amino Acids, Sulfur↗
PubMed1978

Partial "feedback control" of beta-hydroxy-beta-methylglutaryl coenzyme A reductase activity in primary hepatocellular carcinomas.

The activity of beta-hydroxy-beta-methylglutaryl coenzyme A reductase, the rate-controlling enzyme of cholesterol synthesis, was studied in normal livers and in 64 primary hepatocellular carcinomas from rats fed a basal diet or a diet containing either 2% cholestyramine or 5% cholesterol. The average enzyme activity in hepatocellular carcinomas from rats fed the basal diet was more than twice that in normal liver. Dietary cholesterol caused a reduction in activity to one-ninth of the normal hepatic enzyme activity, whereas cholestyramine feeding resulted in a 7-fold increase above the basal level. The data tended to confirm the previously documented observation that "diet-induced feedback inhibition" of cholesterol synthesis is not expressed in hepatomas, since the enzyme activity was reduced only slightly in cancers from rats fed cholesterol. However, the activities from cancers of cholestyramine-fed rats were 2.7 times greater than those from cholesterol-fed rats. Thus, a degree of control was clearly demonstrable, although it represented only 4% of that seen in normal liver. To our knowledge this is the first report of at least partial "feedback control" of beta-hydroxy-beta-methylglutaryl coenzyme A reductase activity in hepatocellular carcinomas grown in vivo.

Animals↗
PubMed1976

Fibrous histiocytoma of the bladder.

A case report of a fibrous histiocytoma of the bladder that presented as total, gross, painless hematuria with compression of the intramural ureter is described. Important pathologic aspects are presented and histiocytic tumors are discussed briefly. Any histiocytic tumor not related to a disease of lipid metabolism is rare and we have found no previous report of a fibrous histiocytoma of the bladder.

Histiocytoma, Benign Fibrous↗
PubMed1976

Importance of sarcosine formation in methionine methyl carbon oxidation in the rat.

Experiments in vitro using rat liver slices indicated that the incorporation of the methionine methyl carbon into sarcosine and serine was dependent upon available glycine and most probably involves glycine methyltransferase. Although the sarcosine methyl carbon was rapidly oxidized to CO2, its formation accounted for only a small proportion of the oxidation of the methionine methyl carbon to CO2 under these conditions. In vivo experiments using a sarcosine trapping pool with 0.3% to 3.0% L-[methyl-14C]methionine in the diet indicated that from 5% to 14% of the absorbed methionine methyl carbon was metabolized via sarcosine, and that this accounted for only 10% to 20% of the observed oxidation of the methyl carbon to CO2. The adaptive response of the rat to high levels of dietary methionine, as indicated by greater oxidation of the methyl carbon to CO2, is in part due to increased sarcosine synthesis. The failure of supplemental glycine to stimulate oxidation of the methionine methyl carbon to CO2 in rats receiving 3% methionine plus 10% sarcosine may be due to sufficient glycine being produced from sarcosine metabolism.

Acetates↗
PubMed1976

Significance of choline synthesis in the oxidation of the methionine methyl group in rats.

Experiments were conducted to assess the significance of de novo choline synthesis in the oxidative metabolism of the methyl group of L-methionine in the rat. Comparison of the rates of 14CO2 production by rats fed diets containing equimolar or equal methyl loads of [methyl-14C]methionine, [methyl-14C] choline, [methyl-14C] betaine and [methyl-14C] sarcosine revealed that the methyl groups of choline, betaine and sarcosine were oxidized at rates nearly equivalent to or exceeding that of the methionine methyl group. However, the results of a second series of in vivo experiments using non-radioactive choline or betaine as intermediary trapping pools indicated that little newly formed radioactive choline was released from tissue phospholipid choline during the period of rapid 14CO2 production from [14CH3] methionine. Incorporation of the methionine methyl group into phospholipid choline by incubated liver slices was strongly inhibited by 2-methoxyethanol without a parallel inhibition of methionine methyl group oxidation. Results of these in vitro studies also indicated that the metabolic pathway responsible for the transfer of the methionine methyl group into choline and that responsible for its oxidation to CO2 differ widely in the ease with which they can be saturated by L-methionine. It is concluded that essentially all of the methionine methyl group oxidation in vitro and that occurring during the absorptive period in vivo must depend primarily on pathways other than those leading to the synthesis of choline.

Adaptation, Physiological↗