Alcohol-mediated effects on the level of cytochrome P-450 and heme biosynthesis in cultured rat hepatocytes

Lane, Stanley E.; Stewart, Michelle

doi:10.1016/0304-4165(83)90232-5

Cited by 16 publications

(5 citation statements)

References 28 publications

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“…A single large dose of ethanol has been shown to induce hepatic 5-aminolaevulinate synthase transiently in rats (Shanley et al, 1968;Rubin et al, 1970;Held, 1977) and humans (Shanley et al, 1969) and in cultured rat hepatocytes (Lane & Stewart, 1983). In contrast, ethanol caused little to no induction of 5-aminolaevulinate synthase in primary cultures of chicken-embryo hepatocytes ( Fig.…”

Section: Discussionmentioning

confidence: 91%

Induction of 5-aminolaevulinate synthase by two- to five-carbon alcohols in cultured chick-embryo hepatocytes. Relationship to induction of cytochrome P-450

Sinclair¹,

Zaitlin²,

Smith³

et al. 1986

Biochemical Journal

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The induction of 5-aminolaevulinate synthase and of cytochrome P-450 by short-chain aliphatic alcohols was compared in primary cultures of chicken-embryo hepatocytes. Isopropyl alcohol, isobutanol, pentan-1-ol and isopentanol alone caused up to a 4-fold increase in 5-aminolaevulinate synthase, whereas ethanol and propan-1-ol did not. Induction of the synthase by isopentanol was maximal at 8 h, and reached a plateau thereafter, whereas the activity induced by 2-propyl-2-isopropylacetamide continued to increase for 20 h. In the presence of 3,4,3',4'-tetrachlorobiphenyl, an inhibitor of haem synthesis at the uroporphyrinogen decarboxylase step, synergistic induction of 5-aminolaevulinate synthase was observed with all the alcohols except ethanol. Ethanol, but not isopentanol, decreased the extent of induction of 5-aminolaevulinate synthase by 2-propyl-2-isopropylacetamide and 3,4,3',4'-tetrachlorobiphenyl (50% decrease at 112 mM-ethanol). Total protein synthesis was not inhibited by ethanol in these cells. The composition of porphyrins was determined after treatment of cells with ethanol, isopentanol or 2-propyl-2-isopropylacetamide. Untreated cells, when incubated with 5-aminolaevulinate for 6 h, accumulated mainly protoporphyrin. However, when cells were pretreated with ethanol, isopentanol or 2-propyl-2-isopropylacetamide for 20 h, and 5-aminolaevulinate was added, 8- and 7-carboxyporphyrins increased, whereas protoporphyrin decreased. The dose responses for induction of either 5-aminolaevulinate synthase or cytochrome P-450 after a 20 h exposure to 3- to 5-carbon alcohols were identical. The results indicate that: simple alcohols can induce both enzymes; hydrophobicity increases their effectiveness; and induction of both enzymes are probably mediated by a common mechanism.

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Section: Discussionmentioning

confidence: 91%

Induction of 5-aminolaevulinate synthase by two- to five-carbon alcohols in cultured chick-embryo hepatocytes. Relationship to induction of cytochrome P-450

Sinclair¹,

Zaitlin²,

Smith³

et al. 1986

Biochemical Journal

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“…The drug is also known to increase the activity of the enzyme in rat liver after chronic (Rubin et al, 1970;Teschke et al, 1987), and in human leukocytes after acute (McColl et al, 1980), administration. In isolated cell systems, however, the effects of the drug are variable, with inhibition in isolated rabbit reticulocytes (Ibrahim et al, 1979) and cultured chick-embryo hepatocytes (Sinclair et al, 1986) and induction in this latter system (Geiger & Meyer, 1980) and in cultured rat hepatocytes (Lane & Stewart, 1983). These controversial findings also clearly require further experimental scrutiny.…”

Section: General Conclusion and Commentsmentioning

confidence: 99%

Effects of acute ethanol administration on rat liver 5-aminolaevulinate synthase activity

Badawy

Morgan

Davis

1989

Biochemical Journal

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1. Liver 5-aminolaevulinate (ALA) synthase activity of 24 h-starved rats is maximally increased at 4 h after intraperitoneal administration of a 1.6 g/kg body wt. dose of ethanol. Larger doses cause a dose-dependent decrease in the extent of this stimulation, exhibiting a reciprocal relationship with an elevation of hepatic haem concentration, as suggested by the simultaneous increase in the haem saturation of tryptophan pyrrolase. 2. ALA synthase induction by ethanol is abolished if the above increase in pyrrolase saturation with haem is enhanced by theophylline, but is potentiated when the increase in the haem saturation is inhibited by anti-lipolytic agents. 3. ALA synthase induction by ethanol is also inhibited by inhibitors of alcohol dehydrogenase and aldehyde dehydrogenase. Acetaldehyde and acetate are, however, not responsible; they both decrease ALA synthase activity and increase the haem saturation of tryptophan pyrrolase. These latter effects of acetaldehyde are not mediated by acetate. 4. ALA synthase activity is also stimulated by succinate, which, however, also increases the haem saturation of tryptophan pyrrolase. 5. Ethanol does not influence the rate of ALA synthase degradation. 6. It is suggested that ethanol increases rat liver ALA synthase activity as a result of its own metabolism by the alcohol dehydrogenase-dependent pathway by a mechanism not involving decreased degradation of the former enzyme or the participation of the metabolites acetaldehyde and acetate.

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“…Some have proposed that this effect is secondary to depletion of a heme regulatory pool, which is depleted during increased formation of cytochrome(s) P‐450 [15]. In rat hepatocyte cultures, the addition of 16 mM ethanol for 24 h, causes a three‐fold increase in the activity of ALAS1 [17]. In humans, increased ALAS1 activity may lead to the accumulation of neuro‐ and dermato‐toxic intermediates of the heme biosynthetic pathway, such as may occur in the porphyrias [1,18–20].…”

Section: Introductionmentioning

confidence: 99%

Tissue‐specific expression of ALA synthase‐1 and heme oxygenase‐1 and their expression in livers of rats chronically exposed to ethanol

et al. 2008

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5-Aminolevulinic acid synthase-1 (ALAS1) and heme oxygenase-1 (HO-1) are the rate-controlling enzymes for heme biosynthesis and degradation, respectively. Expression of these two genes showed tissue-specific expression pattern at both mRNA and protein levels in selected non-treated rat tissues. In the livers of rats receiving oral ethanol for 10 weeks, ALAS1 mRNA levels were increased by 65%, and the precursor and mature ALAS1 protein levels were increased by 1.8-and 2.3-fold, respectively, while no changes were observed in HO-1 mRNA and protein levels, compared with pair-fed controls. These results provide novel insights into the effects of chronic ethanol consumption on hepatic heme biosynthesis and porphyrias.

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Alcohol-mediated effects on the level of cytochrome P-450 and heme biosynthesis in cultured rat hepatocytes

Cited by 16 publications

References 28 publications

Induction of 5-aminolaevulinate synthase by two- to five-carbon alcohols in cultured chick-embryo hepatocytes. Relationship to induction of cytochrome P-450

Induction of 5-aminolaevulinate synthase by two- to five-carbon alcohols in cultured chick-embryo hepatocytes. Relationship to induction of cytochrome P-450

Effects of acute ethanol administration on rat liver 5-aminolaevulinate synthase activity

Tissue‐specific expression of ALA synthase‐1 and heme oxygenase‐1 and their expression in livers of rats chronically exposed to ethanol

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