Ethanol-mediated increase in cytochrome p-450 in cultured hepatocytes

Sinclair, Jacqueline F.; Sinclair, Peter R.; Smith, Elizabeth F.; Bement, William J.; Pomeroy, Joanne S.; Bonkowsky, Herbert L.

doi:10.1016/0006-2952(81)90418-4

Cited by 60 publications

(27 citation statements)

References 13 publications

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“…Chronic ethanol administration provoked small rises in contents of liver microsomal hemoproteins; a 1.26-fold increase of cytochrome bs and a 1.38-fold increase of cytochrome P-450. The enhancement of cytochrome b5 content in ethanol-fed rats may be due to the increase in electron transport to cytochrome P-450, of which content increased in relation to ethanol oxidation [27]. Chronic ethanol intake resulted in a 2-fold elevation of NADH content in rat livers but had no effect on the content of NAD.…”

Section: Analysis Of Hemoprotein Contentmentioning

confidence: 94%

Chronic ethanol administration decreases fatty acyl‐CoA desaturase activities in rat liver microsomes

1984

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The A'-desaturase system in liver microsome from rats treated chronically with ethanol was studied. Stearoyl-CoA desaturase activity decreased by 80% and palmitoyl-CoA desaturase activity was not detectable in microsomes from ethanol-fed rats, while activities of electron transport components such as NADH-cytochrome c and NADH-ferricyanide reductases remained unchanged. However, chronic ethanol administration resulted in an adaptive induction of the activity of NADPH-cytochrome c reductase and the contents of cytochrome by and P-450. The activity of the terminal component (cyanide-sensitive factor; CSF) of the desaturase system was greatly depressed by ethanol treatment. The NADH/NAD ratio in microsomes of ethanol-fed rats increased over 2-fold. These results suggest that, during chronic ethanol ingestion, decreased activities of A'-desaturases are due mainly to a decreased content of the terminal component of the desaturase system.

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Section: Analysis Of Hemoprotein Contentmentioning

confidence: 94%

Chronic ethanol administration decreases fatty acyl‐CoA desaturase activities in rat liver microsomes

1984

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“…The EROD and BROD activities were determined by measuring the formation of resorufin as described previously [55]. The mitoplasts were isolated by treating the mitochondrial fraction with 0.0075% digitonin and isolation through a sucrose cushion.…”

Section: Catalytic Activitymentioning

confidence: 99%

Mitochondrial targeting of intact CYP2B1 and CYP2E1 and N‐terminal truncated CYP1A1 proteins in Saccharomyces cerevisiae − role of protein kinase A in the mitochondrial targeting of CYP2E1

et al. 2007

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Previously we showed that intact rat cytochrome P450 2E1, cytochrome P450 2B1 and truncated cytochrome P450 1A1 are targeted to mitochondria in rat tissues and COS cells. However, some reports suggest that truncated cytochrome P450 2E1 is targeted to mitochondria. In this study, we used a heterologous yeast system to ascertain the conservation of targeting mechanisms and the nature of mitochondria‐targeted proteins. Mitochondrial integrity and purity were established using electron microscopy, and treatment with digitonin and protease. Full‐length cytochrome P450 2E1 and cytochrome P450 2B1 were targeted both to microsomes and mitochondria, whereas truncated cytochrome P450 1A1 (+ 5 and + 33/cytochrome P450 1A1) were targeted to mitochondria. Inability to target intact cytochrome P450 1A1 was probably due to lack of cytosolic endoprotease activity in yeast cells. Mitochondrial targeting of cytochrome P450 2E1 was severely impaired in protein kinase A‐deficient cells. Similarly, a phosphorylation site mutant cytochrome P450 2E1 (Ser129A) was poorly targeted to the mitochondria, thus confirming the importance of protein kinase A‐mediated protein phosphorylation in mitochondrial targeting. Mitochondria‐targeted proteins were localized in the matrix compartment peripherally associated with the inner membrane and their ethoxyresorufin O‐dealkylation, erythromycin N‐demethylase, benzoxyresorufin O‐dealkylation and nitrosodimethylamine N‐demethylase activities were fully supported by yeast mitochondrial ferredoxin and ferredoxin reductase.

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“…Cytochromes P-450 and P-448 were determined by the CO difference spectral assay (20). Benzphetamine-N-demethylase and 7-ethoxyresorufin-O-deethylase activities, which are assays of cytochrome P-450 and cytochrome P-448 isozymes, respectively, were measured spectrofluorometrically in cell homogenates as described previously (21).…”

mentioning

confidence: 99%

Modification of chromium(VI)-induced DNA damage by glutathione and cytochromes P-450 in chicken embryo hepatocytes.

Cupo¹,

Wetterhahn²

1985

Proc. Natl. Acad. Sci. U.S.A.

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The role ofglutathione and cytochrome P-450 in the production of DNA damage by chromium(VI) was examined In chicken embryo hepatocytes by the alkaline elution technique. Cellular levels of glutathione and cytochrome P-450 were altered by treating the hepatocytes with N-acetyl-Lcysteine, buthionine sulfoximine, isopentanol, or 8-naphthoflavone. A dramatic increase in chromium(VI)-induced DNA strand breaks was observed after increasing glutathione levels in the cells. Chromium(VI)-induced DNA strand breaks were even more numerous when the level of cytochrome P-450 was also increased. Upon depletion of glutathione levels and induction ofcytochrome P-450 or cytochrome P 448, little or no DNA strand breaks or DNA interstrand cross-links were observed after chromium(VI) treatment. Chromium(VI)-induced DNA-protein cross-links generally decreased after either increases or decreases in cellular levels of glutathione or cytochrome P-450 or P-448. These results suggest that glutathione enhances chromium(VI)-induced DNA damage through metabolic activation of chromium(VI). The possible production of reactive chromium species upon metabolism by glutathione and cytochrome P-450 or P448 and their involvement in DNA damage is discussed.Chromium(VI) compounds are recognized as carcinogens in humans and animals (1) and as mutagens in bacterial and mammalian cell systems (2). Chromium(VI) causes DNA strand breaks and cross-links in vivo and in cultured cells (3)(4)(5)(6). It has been proposed that cellular metabolism of chromium(VI) compounds is necessary for DNA damage, since chromium(VI) does not react with isolated DNA under physiological conditions (7). The DNA-damaging ability of other carcinogenic agents has been shown to be modulated by metabolic pathways such as the cytochrome P450 system, sulfotransferases, and glutathione (GSH) (8). Changes in cellular levels of cytochromes P-450 alter the levels of DNA damage produced by carbon tetrachloride (9), benzo-[a]pyrene (10), and dimethylnitrosamine (11) in rodents.In vitro studies have identified several cellular components that are capable of metabolizing chromium(VI) (12-14). Rat liver microsomes contain a NADPH-dependent chromium(VI) reductase activity (15). Induction of cytochrome(s) P-450 by phenobarbital enhances the chromium(VI) reductase activity ofliver microsomes; however, induction of cytochrome(s) P-448 by 3-methylcholanthrene has no effect (13). GSH also reduced chromium(VI) in vitro under physiological conditions (12,14). The reaction of GSH with chromium(VI) has been proposed to occur by a two-step mechanism that involves the rapid formation of a chromium(VI) thioester followed by the reduction of the chromium(VI) thioester to chromium(III) (12).The present report describes the effect of altering the intracellular concentrations of cytochrome P450 and P-448 and GSH on chromium(VI)-induced DNA damage in primary cultured chicken embryo hepatocytes. Chromium(VI) treatment is known to produce DNA damage in chicken embryo hepatocytes (5, 6). The hepatocytes ar...

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Ethanol-mediated increase in cytochrome p-450 in cultured hepatocytes

Cited by 60 publications

References 13 publications

Chronic ethanol administration decreases fatty acyl‐CoA desaturase activities in rat liver microsomes

Chronic ethanol administration decreases fatty acyl‐CoA desaturase activities in rat liver microsomes

Mitochondrial targeting of intact CYP2B1 and CYP2E1 and N‐terminal truncated CYP1A1 proteins in Saccharomyces cerevisiae − role of protein kinase A in the mitochondrial targeting of CYP2E1

Modification of chromium(VI)-induced DNA damage by glutathione and cytochromes P-450 in chicken embryo hepatocytes.

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