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Biomedical subjects

C O Abernathy

Publications and source records attributed to C O Abernathy.

At least 37 records · Page 2Linked to original sources
PubMed1979

Immaturity of the biliary excretory system predisposes neonates to intrahepatic cholestasis.

Intrahepatic cholestasis associated with both gram-negative bacterial infections and total parenteral nutrition (TPN) is observed more frequently in neonates than in older children or adults. Factors involved in the pathogenesis of this syndrome are uncertain. The cholestatic effects of gram-negative bacterial infections appear to result from the inhibitory effects of endotoxin on bile flow. Since the adverse effects of both endotoxin and TPN on bile flow involve primarily the bile acid-independent portion, the immaturity of the neonatal hepatic excretory system which an inadequate bile acid-dependent fraction of bile would explain the increased susceptibility of the neonate to endotoxin- and, perhaps, to TPN-induced cholestasis.

Bacterial Infections↗
PubMed1978

Cholestatic effects of cis-chlorprothixene on the perfused rat liver.

The cis-isomer of chlorprothixene (CPX) inhibited the excretory function of the isolated perfused rat liver. It decreased the biliary clearance and transport maximum of sulfobromophthalein (BSP). Calculation of the BSP 'clearance constants' suggested that the primary effect of the drug was on excretion and not uptake. The ability of the drug to inhibit the excretion of indocyanine green suggested that the effects of CPX were not the result of inhibition of hepatic conjugative enzymes. Measurement of 14C-erythritol clearance indicated that the deleterious effects of CPX on bile formation were at the canalicular level and that they were mainly on the bile acid-independent fraction of bile. The data indicated that the adverse effects of CPX were at the excretory level of the hepatocyte.

Animals↗
PubMed1978

Effects of some thioxanthenes on bile formation and organic anion clearance in the perfused rat liver.

Perfusion of the isolated rat liver with cis-thiothixene (THX), cis- or trans-flupenthixol (FPX), and cis- or trans-clopenthixol (CLX) has demonstrated that each of the compounds exerted adverse effects on hepatic excretory function and that their relative order of potency was THX greater than cis- = trans-FPX greater than cis- = trans-CLX. THX caused dose-dependent reductions in bile flow and sulfobromophthalein (BSP) clearance. The 14C-erythritol clearance and bile acid excretion data suggested that the primary effects of THX (10(-5)M) were on the bile acid-independent fraction of bile. The BSP kinetic data indicated that THX mainly affected the excretion of BSP and not its uptake. Since THX also decreased the excretion of indocyanine green, inhibition of hepatic conjugative enzymes did not appear to be responsible for the observed decreases in organic anion excretion. At 2.5 X 10(-5) M, both isomers of FPX reduced bile flow and BSP excretion. It took a higher concentration (7.5 X 10(-5) M) for either isomer of CLX to effect similar reductions.

Animals↗
PubMed1977

Inhibition of Na+, K+-adenosinetriphosphatase by endotoxin: a possible mechanism for endotoxin-induced cholestasis.

Cholestatic jaundice is one complication of nonhepatic gram-negative bacterial infection. The endotoxin of Escherichia coli has been reported to cause cholestasis by inhibiting the bile salt-independent fraction (BSIF) of bile in the perfused rat liver. Accordingly, the effects of lipopolysaccharides (LPS) of E. coli and Salmonella enteritidis on the Na+, K+-adenosinetriphosphatase (ATPase) in canalicular-enriched plasma membranes of rate liver were examined. At 20 microgram/ml, both endotoxins inhibited this enzyme by approximately 40%. Maximal inhibition (70%-80%) occurred at concentrations of greater than or equal to 120 microgram/ml. The LPS of neither organism exerted any effect on the activity of Mg++-ATPase or 5'-nucleotidase in the same preparations. Inhibition by the E. coli LPS appeared to be noncompetitive in nature, and the calculated Ki was 45 microgram/ml. Since the Na+, K+-ATPase may be responsible for the elaboration of BSIF, inhibition of this enzyme could be the underlying mechanism for the endotoxin-induced cholestasis.

Adenosine Triphosphatases↗
PubMed1977

Studies on the effects of C. coli endotoxin on canalicular bile formation in the isolated perfused rat liver.

The impairment of biliary excretory function induced by E. coli endotoxin in the isolated perfused rat liver was studied by investigating its effects on canalicular bile formation. In experiments where no bile salt was infused, endotoxin administration resulted in significant decreases in bile salt-independent bile flow (BSIF) and sulfobromophthalein (BSP) excretion. It also caused dose-dependent decreases in the transport maximum of BSP but did not alter the ability of the liver to concentrate BSP in the bile. At 2 mg./100 ml. it decreased the hepatic removal rate but increased the hepatic storage of the dye. Measurement of 14 C-erythritol clearance and bile salt secretion also revealed that endotoxin significantly reduced the BSIF fraction of bile. The results indicated that the primary effects of endotoxin were on BSIF and BSP excretion.

Animals↗
PubMed1976

Cholestatic effects of Escherichia coli endotoxin endotoxin on the isolated perfused rat liver.

The effects of Escherichia coli endotoxin on the function of the ex vivo perfused rat liver were examined in order to investigate the possible role of circulating endotoxin in the pathogenesis of cholestatic jaundice observed in humans with gram-negative bacterial infections. Endotoxin led to a dose-dependent impairment of bile flow and of sulfobromophthalein (BSP) excretion. The demonstration that indocyanine green excretion was also significantly decreased by endotoxin suggests that the impaired dye excretion was not due to an inhibition of BSP conjugation in the hepatocyte. Analysis of the kinetic data suggested that the effects of endotoxin were on the excretory mechanisms of the hepatocyte. These effects did not seem attributable to endotoxin-mediated changes in perfusate flow since a mechanical reduction in perfusate flow caused no decrease in the excretion of bile or BSP. The results of the present study provide supportive evidence for the hypothesis that circulating endotoxin can adversely affect hepatic function and may contribute to the production of intrahepatic cholestasis seen during bacterial infection. Hepatocyte injury by endotoxin, as judged by the leakage of enzymes from hepatocyte suspensions or from the perfused rat liver, could not be demonstrated.

Animals↗
PubMed1975

The effect of chlordiazepoxide hydrochloride on the isolated perfused rat liver.

The effects of chlordiazepoxide-hydrochloride (CDZ) on the isolated perfused rat liver were examined. CDZ administration decreased bile flow, biliary excretion of sulfobromophthalein (BSP) and hepatic uptake of BSP. The addition of CDZ to the perfusate of livers obtained from phenobarbital (Pb) pretreated rats led to 50% greater reductions in bile flow, concentration of BSP in bile and hepatic uptake of BSP. The adverse effects of CDZ on BSP excretion per g liver, however, did not appear to be enhanced by Pb pretreatment. The complex nature of the interrelationship of the effects of Pb and of CDZ on the control liver prevented differentiation of the role of CDZ from that of a metabolite on the adverse effect on liver function.

Animals↗
PubMed1975

The toxicity of thioxanthene neuroleptics to isolated rat liver cells.

A series of thioxanthenes was tested for cytotoxicity to isolated rat hepatocytes, as measured by the loss of an intracellular enzyme (GOT) to the surrounding medium. The relative order of potency was found to be: SKF 10812 greater than cis- = trans-chlorprothixene = N-756A greater than cis- = trans-flupenthixol greater than xanthiol greater than methixene = cis- = trans-clopenthixol = N-716 greater than N-710. The presence of an unsaturated exocyclic bond increased the apparent toxicity as did the presence of a substituent (trifluoromethyl, chlorine, bromine) at the two position of the tricyclic nucleus. The trifluoromethyl substituted thioxanthenes were three to four times more potent than their halogenated analogs, but there were no differences in potency among the halogenated (chlorine or bromine) thioxanthenes. Compounds which had a dimethylaminopropylidene side chain were five to six times stronger in causing enzyme leakage than were their analog which had a hydroxyethylpiperazinylpropylidene side chain. Although only the cis-isomers of each compound are highly active neuroleptics, both isomers were equipotent at causing the efflux of GOT from rat hepatocytes.

Animals↗
PubMed1973

Pyrethroid insecticides: esterase cleavage in relation to selective toxicity.

The ester group of primary alcohol chrysanthemates is cleaved by mouse hepatic microsomal esterases, more rapidly for the (+)-trans than for the (+)-cis isomers. Substrate-specificity and inhibition studies in vivo establish that these pyrethroid-hydrolyzing esterases probably contribute to the low mammalian toxicity of bioresmethrin and other (+)-trans chrysanthemate insecticide chemicals derived from primary alcohols.

Animals↗