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C O Abernathy

Publications and source records attributed to C O Abernathy.

At least 19 recordsLinked to original sources
PubMed1999

Arsenic: health effects, mechanisms of actions, and research issues.

A meeting on the health effects of arsenic (As), its modes of action, and areas in need of future research was held in Hunt Valley, Maryland, on 22-24 September 1997. Exposure to As in drinking water has been associated with the development of skin and internal cancers and noncarcinogenic effects such as diabetes, peripheral neuropathy, and cardiovascular diseases. There is little data on specific mechanism(s) of action for As, but a great deal of information on possible modes of action. Although arsenite [As(III)] can inhibit more than 200 enzymes, events underlying the induction of the noncarcinogenic effects of As are not understood. With respect to carcinogenicity, As can affect DNA repair, methylation of DNA, and increase radical formation and activation of the protooncogene c-myc, but none of these potential pathways have widespread acceptance as the principal etiologic event. In addition, there are no accepted models for the study of As-induced carcinogenesis. At the final meeting session we considered research needs. Among the most important areas cited were a) As metabolism and its interaction with cellular constituents; b) possible bioaccumulation of As; c) interactions with other metals; d) effects of As on genetic material; e) development of animal models and cell systems to study effects of As; and f) a better characterization of human exposures as related to health risks. Some of the barriers to the advancement of As research included an apparent lack of interest in the United States on As research; lack of relevant animal models; difficulty with adoption of uniform methodologies; lack of accepted biomarkers; and the need for a central storage repository for stored specimens.

Arsenic↗
PubMed1996

Is ingested inorganic arsenic a "threshold" carcinogen?

Ingested inorganic arsenic (As) is known to be a human carcinogen. An intriguing question is whether there is a threshold for the carcinogenic effects of As, i.e., is there a level below which it does not induce the development of cancer(s)? This Roundtable will discuss the United States Environmental Protection Agency's As risk assessment using the Taiwan data from different viewpoints. It will also consider the hypothesis that there is a threshold for As and data for or against this hypothesis. For example, some scientists believe that epidemiological data cannot answer this question, while others feel that different study designs and larger sampling will provide adequate data. Reasons for each position are given. This Roundtable discussion demonstrates the controversy surrounding the use of the Taiwan data for risk assessment.

Arsenic Poisoning↗
PubMed1992

Effects of bile salt infusion on chlorpromazine-induced cholestasis in the isolated perfused rat liver.

The present study has demonstrated that tauroursodeoxycholate (TUDC), but not taurocholate, can reverse chlorpromazine (CPZ)-induced cholestasis in the isolated perfused rat liver. At an infusion rate of 1.5 mumol/min, TUDC led to restoration of bile flow in the perfused rat liver made cholestatic by the addition of 250 microM CPZ. This reversal was accompanied by an increased excretion of CPZ and its metabolites. A higher infusion rate of 5.0 mumols TUDC/min, however, led to only a transient increase in bile flow and to no increase in CPZ excretion. In contrast to the effects of TUDC, infusion of taurocholate led to an exacerbation of CPZ-induced cholestasis. The differences in the efficacy of the two bile salts may be due to their relative detergent (hydrophobic) properties.

Animals↗
PubMed1992

Drug-induced cholestasis in the perfused rat liver and its reversal by tauroursodeoxycholate: an ultrastructural study.

Chlorpromazine at a concentration of 250 microM and estradiol-17 beta-D-glucuronide at 17.5 microM on infusion led to a sharp reduction in bile flow by the in vitro perfused rat liver. This was accompanied by fragmentation and a loss of canalicular microvilli, dilatation of canaliculi, and thickening of pericanalicular ectoplasm. Less prominent were the smooth endoplasmic reticulum dilatation, lysosomal lamination, and the appearance of amorphous bile in hepatocyte cytoplasm. The bile flow and electron microscopy appearance were restored to normal by infusion of tauroursodeoxycholate in a concentration of 5 mumols/min for the estradiol-17 beta-D-glucuronide-induced cholestasis and 1.5 mumol/min for the chlorpromazine-induced cholestasis. Changes in ultrastructure paralleled changes in bile flow. These observations demonstrate the feasibility of electron microscopy studies on the perfused liver, and the rapidity with which cholestatic changes appear.

Animals↗
PubMed1990

Estradiol-17 beta-D-glucuronide (E-17G) cholestasis in perfused rat liver: fate of E-17G and choleretic responses to bile salts.

This study was designed to test the hypothesis that increasing the infusion rate of bile salts could overcome drug-induced cholestasis. Cholestasis was induced by administration of 17.5 mumol/L estradiol-17 beta-D-glucuronide during the infusion of taurocholate, tauroursodeoxycholate or dehydrocholate at 20 nmol/min/gm liver. After 30 min, a bolus of 10 mumol of the bile salts was added to the perfusate, and the infusion rate of each bile salt was increased. Taurocholate at a rate of 62 or 125 nmol/min/gm liver, caused a prompt dose-dependent increase of the depressed bile flow and bile salt excretion. A higher rate of taurocholate infusion (180 nmol/min/gm liver) was less effective than either the 62 or 125 rate in increasing bile flow. Infusion of tauroursodeoxycholate at 250 or 390 nmol/min/gm liver also led to a dose-dependent recovery. Further increase of tauroursodeoxycholate infusion rate of 580 nmol/min/gm liver did not provide any additional recovery in bile flow. Dehydrocholate, at rates of 62 or 125 nmol/min/gm liver, gave only a slight enhancement of bile flow. Both taurocholate and tauroursodeoxycholate caused a marked removal of the estradiol-17 beta-D-glucuronide, which had accumulated in the liver. At lower taurocholate infusion rates, the estradiol-17 beta-D-glucuronide was excreted mainly in the bile. At the highest rate, however, biliary excretion of estradiol-17 beta-D-glucuronide declined significantly, and a marked back-efflux of the estrogen into the perfusate was noted. In contrast, tauroursodeoxycholate led to enhanced biliary estradiol-17 beta-D-glucuronide excretion at all increased tauroursodeoxycholate infusion rates and to only a small increase in back-efflux of estradiol-17 beta-D-glucuronide at the two highest tauroursodeoxycholate infusion rates.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Acrylamide: its metabolism, developmental and reproductive effects, genotoxicity, and carcinogenicity.

Monomeric acrylamide is an important industrial chemical primarily used in the production of polymers and copolymers. It is also used for producing grouts and soil stabilizers. Acrylamide's neurotoxic properties have been well documented. This review will focus on pertinent information concerning other, non-neurotoxic, effects observed after exposure to acrylamide, including: its genotoxic, carcinogenic, reproductive, and developmental effects. It will also cover its absorption, metabolism, and distribution. The data show that acrylamide is capable of inducing genotoxic, carcinogenic, developmental, and reproductive effects in tested organisms. Thus, acrylamide may pose more than a neurotoxic health hazard to exposed humans. Acrylamide is a small organic molecule with very high water solubility. These properties probably facilitate its rapid absorption and distribution throughout the body. After absorption, acrylamide is rapidly metabolized, primarily by glutathione conjugation, and the majority of applied material is excreted within 24 h. Preferential bioconcentration of acrylamide and/or its metabolites is not observed although it appears to persist in tests and skin. Acrylamide can bind to DNA, presumably via a Michael addition-type reaction, which has implications for its genotoxic and carcinogenic potential. The available evidence suggests that acrylamide does not produce detectable gene mutations, but that the major concern for its genotoxicity is its clastogenic activity. This clastogenic activity has been observed in germinal tissues which suggest the possible heritability of acrylamide-induced DNA alterations. Since there is 'sufficient evidence' of carcinogenicity in experimental animals as outlined under the U.S. EPA proposed guidelines for carcinogen risk assessment, acrylamide should be categorized as a 'B2' carcinogen and therefore be considered a 'probable human carcinogen.' The very limited human epidemiological data do not provide sufficient evidence to enable one to judge the actual carcinogenic risk to humans. Acrylamide is able to cross the placenta, reach significant concentrations in the conceptus and produce direct developmental and post-natal effects in rodent offspring. It appears that acrylamide may produce neurotoxic effects in neonates from exposures not overtly toxic to the mothers. Acrylamide has an adverse effect on reproduction as evidenced by dominant lethal effects, degeneration of testicular epithelial tissue, and sperm-head abnormalities.

Abnormalities, Drug-Induced↗
PubMed1987

Effects of lipid A content, hydrocortisone and polymyxin B on endotoxin-induced decreases in in vivo drug metabolism.

Using hexobarbital sleeping and zoxazolamine paralysis time as indices of in vivo hepatic drug metabolism, the effects of endotoxin on drug action appear to be time- and dose-dependent and the lipid A moiety of endotoxin appears to be responsible for its inhibitory effects. These studies have also demonstrated that polymyxin B can ameliorate the adverse effects of endotoxin on drug metabolism. Since hydrocortisone protects mice from endotoxin lethality, but does not alter the prolongation of hexobarbital sleeping time caused by endotoxin, it is possible to separate the lethal effects of endotoxin from its effects on drug metabolism.

Animals↗
PubMed1986

Prevention of the toxicity of erythromycin estolate in the perfused rat liver by endotoxin.

The possibility that endotoxin pretreatment could prevent the hepatotoxic effects of erythromycin estolate (EE) was investigated using the isolated perfused rat liver. The addition of E. coli endotoxin (25 micrograms/ml) to the perfusate, 30 min prior to EE administration at 150 or 200 microM, significantly ameliorated the decreases in bile and perfusate flow caused by either concentrations of the drug in control liver preparations. This phenomenon was also studied using liver isolated from rats pretreated in vivo with endotoxin for three days. In these preparations, EE at both concentrations did not alter bile flow and caused reductions of perfusate flow which were far less than those observed in untreated control livers. Furthermore, in livers from endotoxin-treated rats EE induced less reduction of bile acid excretion and, at 150 microM, it did not increase the bile to perfusate ratio of sucrose seen in control preparations after the drug, which may be an expression of altered hepatocytic membrane permeability. Since it is known that both endotoxin and EE interact with membranes, it is suggested that the "protective" effects of endotoxin may occur at the membrane level.

Animals↗
PubMed1986

Effects of H2-blocking agents on hepatocytes in vitro: correlation with potential for causing hepatic disease in patients.

The adverse effects on an in vitro model of oxmetidine, an H2-blocking agent which has been shown to produce hepatic injury in 1 to 4% of patients, were compared with those of cimetidine and ranitidine which have led to only rare instances of hepatic injury. Suspensions of hepatocytes, freshly isolated from Sprague-Dawley rats, were exposed to the three drugs. Oxmetidine, in concentrations of 3 X 10(-3) M or greater, led to leakage of AST into the medium after 4 hr of incubation. Ranitidine and cimetidine, in concentrations up to 5 X 10(-3) M, produced no identifiable leakage. Pretreatment of rats with phenobarbital, 3-methylcholanthrene, or SKF 525A resulted in no significant enhancement or inhibition of the oxmetidine effects. These results suggest that the adverse effects of oxmetidine on the hepatocytes are produced by the native compound, not a metabolite. The positive correlation between in vivo and in vitro toxicity supports the view that in vitro testing may prove to be of use in predicting the hepatotoxic potential of a drug.

Animals↗
PubMed1985

Characterization of the effects of erythromycin estolate and erythromycin base on the excretory function of the isolated rat liver.

To investigate the mechanisms of erythromycin cholestasis, the effects of erythromycin estolate (EE) on the excretory function of the isolated perfused rat liver and on liver plasma membrane (LM) preparations were studied and compared to those of erythromycin base (EB) and lauryl sulfate (LS), added alone or in combination. EE (at 125 to 200 microM) caused dose-dependent reductions of bile and perfusate flows, bile acid (BA) excretion, and biliary BA concentration. The alterations of the excretory function were only in part due to the decreased perfusate flow. In contrast, both 200 and 300 microM concentrations of EB elicited similar choleretic responses, which were presumably related to the osmotic activity of the drug excreted in the bile. LS did not affect hepatic excretory functions. However, the simultaneous addition of EB and LS resulted in a rate of bile flow lower than that observed with EB alone. EE, but not EB, increased canalicular permeability to [14C]sucrose as measured by bile to plasma (B:P) ratio. Neither drugs altered [14C]erythritol B:P ratio. In LM preparations both Na+,K+- and Mg2+-ATPase activities were inhibited in a dose-dependent manner by EE, but not by EB. The data suggest that EE could affect bile flow by inhibiting cotransport of Na+ and BA and by altering LM permeability and support the view that the effect of erythromycins on the liver may be related to their surface activity.

Adenosine Triphosphatases↗
PubMed1982

Effects of endotoxin tolerance on hepatic excretory function: in vivo study.

Induction of endotoxin tolerance in rats led to reductions in bile flow and BSP excretion. BSP serum retention or storage of BSP in the liver was not affected. Although serum alanine aminotransferase (ALT) activity was slightly elevated in endotoxin-tolerant rats, the levels of serum aspartate amino-transferase (AST) and hepatic 5'-nucleotidase were normal. These in vivo data support the validity of in vitro studies demonstrating the cholestatic effect of endotoxin and the viewpoint that endotoxin may be responsible for the cholestatic jaundice associated with Gram-negative bacterial infections.

Animals↗
PubMed1982

Effects of acute and chronic endotoxin treatment on glucagon and insulin receptors on rat liver plasma membranes.

The effects of acute and chronic endotoxin treatment on the plasma levels of insulin and glucagon and their binding to rat liver plasma membranes were examined. Both acute and chronic endotoxin administration increased plasma glucagon levels and decreased the glucagon to insulin molar ratio. Acute, but not chronic, endotoxin decreased blood glucose and insulin levels. Glucagon binding was increased in membranes prepared from the acutely treated rats. However, in membranes obtained from rats treated chronically with endotoxin, only insulin binding was increased. The increases in the binding of both insulin and glucagon were the result of increases in receptor sites.

Animals↗
PubMed1981

Endotoxin protects against chlorpromazine-induced cholestasis in the isolated perfused rat liver.

Induction of endotoxin tolerance or acute chlorpromazine treatment caused a decrease in bile and perfusate flow in the isolated perfused rat liver. The primary effects of each appeared to be on the bile acid-independent fraction of bile. Both the induction of endotoxin tolerance and the in vitro treatment of the perfused rat liver with endotoxin partially blocked the adverse effects of chlorpromazine on bile formation and perfusate flow. Although the "protective" effects of the in vitro endotoxin treatment were dose-dependent, the protection afforded by endotoxin tolerance was greater. Preincubation of isolated hepatocytes with endotoxin, before the addition of chlorpromazine, caused dose-dependent reductions in the chlorpromazine-induced release of aspartate transaminase. However, neither the incubation of endotoxin with chlorpromazine, before addition of membranes isolated from control rats, nor isolation of membranes from endotoxin-tolerant rats affected the inhibitory effects of chlorpromazine on sodium, potassium-, or magnesium-activated adenosine triphosphatase. If endotoxin exerts its protective effects at the membrane level, these data suggest that endotoxin is able to protect the intact, but not the isolated, hepatocyte membrane or that inhibition of adenosine triphosphatases by chlorpromazine is not important in the adverse effects of chlorpromazine on the perfused rat liver and isolated rat hepatocytes.

Animals↗
PubMed1980

Effects of endotoxin-tolerance on in vivo drug metabolism in mice.

Acute doses of endotoxin and the induction of endotoxin-tolerance lowered the apparent in vivo rates of hexobarbital and zoxazolamine metabolism in mice. Acute doses of endotoxin increased the duration of narcosis induced by these two compounds to a greater extent than did induction of the endotoxin-tolerant state. In endotoxin-tolerant mice, however, acute endotoxin treatment did not extend hexobarbital sleeping or zoxazolamine paralysis times beyond those noted in endotoxin-tolerant mice given no acute endotoxin.

Animals↗