Ethanol Impairs Biliary Lysosomal Enzyme Release in Rats

Sewell, R. B.; Grinpukel, S.; Yeomans, Neville D

doi:10.1111/j.1440-1681.1986.tb02416.x

Cited by 6 publications

(6 citation statements)

References 20 publications

(18 reference statements)

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“…The increase which we have demonstrated in biliary excretion of lysosomal contents using the repeat dose pretreatment regimen may thus reflect an appropriate response of the lysosome to an accumulation of abnormal constituents induced by perhexilene. In the single dose study, perhexilene reversed the inhibition in biliary lysosomal enzyme output due to acute ethanol dosage; this inhibition has been reported previously using the IPRL model at this ethanol concentration (Sewell et al 1986b). These single dose perhexilene effects may reflect a change at the biliary canaliculus, perhaps to membrane characteristics, rather than changes within the hepatocyte lysosome itself.…”

Section: Discussionsupporting

confidence: 80%

“…In this 5 day pretreatment study, bile flow was not changed by perhexilene, whereas in 1 single dose study bile flow inhibition due to ethanol was reversed to values previously reporl with 0.15 mmol saline controls (Sewell et al 1986b). One other study has examined bile flow bile fistula rats given a perhexilene dose (in propylene glycol) 2-8 times greater; only at the high dose (80 mg/kg) was bile flow increased (Hoenig & Werner 1980a) and there was no effect biliary bile acid excretion.…”

Section: Discussioncontrasting

confidence: 50%

“…Addition of perhexilene (0.6 mg), a dose which induced a 'therapeutic' perhexilene concentration €or less than 30 min, to the perfusate reservoir induced a significant increase in the outputs of lysosomal enzymes into bile (Table 1). Interestingly, with a single dose of perhexilene, bile flow was also significantly increased compared with controls (0.022Yo ethanol), although bile flow in the control (0.022% ethanol) rats was less than in controls previously given 0.15 mol/l saline (Sewell et al 1986b). The liver weights of the perhexilene-treated and control (0.022% v/v ethanol) animals were no different, 8.1 0.8 and 8.8 f 0.5 g, respectively, and the hepatic activities of lysosomal enzymes were not significantly altered by perhexilene.…”

Section: Singie Dose Perhexilenementioning

confidence: 84%

“…Livers were harvested from fed female Sprague-Dawley rats (1 70-235 g) under pentobarbit anaesthesia. The details of the isolated perfused rat liver (IPRL) model have been describc previously (Sewell et al 1986b). In brief, livers were isolated by conventional means and placed a humidified cabinet maintained at 37°C.…”

Section: Experimental Model-the Isolated Perfused Rat Livermentioning

confidence: 99%

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Perhexilene: Effects on Hepatic Lysosomal Function in Rats

Sewell

Horowitz

Grinpukel

et al. 1989

Clin Exp Pharma Physio

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1. Perhexilene, a long-acting anti-anginal drug, can induce adverse effects on the liver which may be dose-dependent. At high concentrations, perhexilene causes marked morphological changes in hepatocyte lysosomes. The current study examined the effect of 'therapeutic' doses of perhexilene on hepatic lysosomal function, particularly the biliary release of lysosomal enzymes, using an isolated perfused rat liver (IPRL) model. 2. Pharmacokinetic studies demonstrated that clearance of single doses of perhexilene by the perfused rat liver was dose-dependent and established a 'therapeutic' dose of 0.6 mg using the IPRL. A 5 day pretreatment regimen of 20 mg/kg per day was shown to produce 'therapeutic' perhexilene concentrations of 150-210 ng/ml. 3. At perhexilene concentrations equating the 'therapeutic' range in man, the major effect of perhexilene was at the biliary pole of the hepatocyte. In 5 day pretreatment dose studies, lysosomal enzyme excretion into bile was markedly increased. In single dose studies, the increase in biliary lysosomal enzyme output partially reflected an increase in bile water production which was not seen with the 5 day pretreatment regimen. Hepatic and perfusate lysosomal enzyme activities were not affected. 4. This selective effect of perhexilene on hepatocyte-to-bile lysosomal excretion may reflect intracellular lysosomal drug localization.

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Section: Discussionsupporting

confidence: 80%

Section: Discussioncontrasting

confidence: 50%

Section: Singie Dose Perhexilenementioning

confidence: 84%

Section: Experimental Model-the Isolated Perfused Rat Livermentioning

confidence: 99%

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Perhexilene: Effects on Hepatic Lysosomal Function in Rats

Sewell

Horowitz

Grinpukel

et al. 1989

Clin Exp Pharma Physio

Self Cite

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“…The effect of alcohol on biliary excretion of dolichols has so far not been investigated, although biliary excretion has been considered to be an important elimination route for dolichols (19). Acute ethanol administration has been shown to decrease biliary lysosomal enzyme output in liver perfusate (20). Chronic ethanol feeding, however, has been shown to have no effect on biliary cholesterol or phospholipid output (21).…”

mentioning

confidence: 99%

Biliary excretion of dolichols and β‐hexosaminidase—Effect of ethanol and glucagon

Humaloja

Salaspuro

Roine

1997

Lipids

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Alcohol has been reported to increase the urinary excretion of dolichols, and urinary dolichols are suggested to be derived from the lysosomes of the renal cells. In the present study we examined the effects of alcohol and glucagon on the biliary excretion of dolichols in rats. Chronic ethanol treatment decreased both biliary dolichol and beta-hexosaminidase excretion. The absolute amount of dolichol excreted into the bile correlated highly significantly with the absolute amount of biliary beta-hexosaminidase. Our results indicate that biliary dolichols are--at least in part--derived from hepatic lysosomes. Decreased biliary dolichol output during chronic alcohol administration suggests that urinary and biliary dolichol excretions are regulated independently of each other.

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Functional and ultrastructural features of ethanol/bile salts interaction in the isolated perfused rat liver

et al. 1995

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We investigated whether bile salts (BS) with different hydrophobic-hydrophilic properties interact with ethanol on bile secretion, enzyme (aspartate transaminase [AST], lactate dehydrogenase [LDH]) release in the perfusate, liver ultrastructure, and vesicular exocytosis in the isolated perfused rat liver. Ethanol (0.1 or 1%) promoted a rapid decrease of bile flow and BS secretion in livers perfused with taurocholate (TCA), the physiologic BS in the rat (-28% decrease of baseline values with 0.1% and -34% with 1% ethanol). The inhibitory effect of ethanol on bile flow and BS secretion was significantly (P < .02) attenuated by perfusing liver with the hydrophilic BS, tauroursodeoxycholate (TUDCA), and it was exacerbated (P < .02) by perfusion with the hydrophobic BS, taurodeoxycholate (TDCA). The release of AST and LDH in the perfusate was unaffected by 0.1% ethanol, but increased threefold to fivefold by 1% ethanol in TCA-perfused livers. This cytolitic effect of ethanol was not observed in TUDCA-perfused livers, but it was enhanced (P < .03) by perfusion with TDCA. No ultrastructural abnormalities were found in either TCA- or TUDCA-perfused livers, with or without 1% ethanol. Only minimal changes were found in livers perfused with TDCA alone, but, in the presence of TDCA, 1% ethanol induces marked mitochondrial damage. The biliary excretion of the fluid phase marker horseradish peroxidase was inhibited by ethanol, an effect reversed by TUDCA (P < .02) and exacerbated by TDCA (P < .04). In conclusion, this study demonstrates that hydrophilic BS such as TUDCA counteract the inhibitory effect of ethanol on bile secretion and vesicular exocytosis as well as the ethanol-induced cytolitic effect in the isolated perfused rat liver. In the presence of hydrophobic BS such as TDCA, the exposure to ethanol promotes a marked inhibition of bile secretion and vesicular exocytosis as well as prominent mitochondrial damage.

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Ethanol Impairs Biliary Lysosomal Enzyme Release in Rats

Cited by 6 publications

References 20 publications

Perhexilene: Effects on Hepatic Lysosomal Function in Rats

Perhexilene: Effects on Hepatic Lysosomal Function in Rats

Biliary excretion of dolichols and β‐hexosaminidase—Effect of ethanol and glucagon

Functional and ultrastructural features of ethanol/bile salts interaction in the isolated perfused rat liver

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