Aminopyrine and biphenyl metabolism in cultured hepatocytes

Sinclair, Jacqueline F.; Wiebkin, Philip; Zaitlin, Linda M.; Smith, Elizabeth F.; Sinclair, Peter R.

doi:10.1016/0006-2952(84)90474-x

Cited by 9 publications

(4 citation statements)

References 15 publications

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“…We have previously shown that C2-C5 alcohols cause a phenobarbital-like induction of cytochrome P-450 in cultured chick-embryo hepatocytes (J. Sinclair et al, 1982aSinclair et al, , 1984. A quantitative analysis of structure-activity relationships demonstrated a linear correlation between induction of cytochrome P-450 and hydrophobicity of the alcohols (Sinclair et al, 1986).…”

Section: Discussionmentioning

confidence: 96%

See 1 more Smart Citation

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: 96%

“…Sinclair et al, 1982a; J. Sinclair et al, 1984). Characteristics of this induction include (a) increases in (i) hydroxylation of biphenyl at the 4-rather than the 2-position, (ii) UDP-glucuronyltransferase activity, (iii) demethylation of benzphetamine and (b) little to no de-ethylation of ethoxyresorufin.…”

Section: Introductionmentioning

confidence: 99%

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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“…Chromium(VI) treatment is known to produce DNA damage in chicken embryo hepatocytes (5,6). The hepatocytes are well suited for these experiments because intracellular levels of the different isozymes of cytochrome P-450 can be increased by f naphthoflavone (16) and isopentanol (17). GSH has been shown to increase in these cells with the induction of cytochrome P-450, but not with induction of cytochrome P-448 (18).…”

Section: In Rodentsmentioning

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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“…Wurden die Hepatozyten 48 Stunden lang mit 3-Methylbutanol-1 inkubiert und danach in frischem Medium für 4 Stunden Diphenyl oder Aminopyrin zugesetzt, so war der Metabolismus im gleichen Maß beschleunigt, wie nach Vorinkubation mit Propylisopropylacetamid, dem stärksten bekannten Enzyminduktor für diese P-450-abhän-gigen Stoffwechselwege. Die Autoren schlossen daraus, dass 3-Methylbutanol-1 als Enzyminduktor im Stoffwechsel von Fremdstoffen in der Leber wirksam werden kann (Sinclair et al, 1984). ), da sie das Enzym Hypoxanthinguaninphosphoribosyltransferase (HGPRT) entweder enthielten oder nicht enthielten.…”

Section: Neurotoxizitätunclassified

Pentanol‐Isomeren [MAK Value Documentation in German language, 2008]

2012

The MAK‐Collection for Occupational Health and Safety

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Veröffentlicht in der Reihe Gesundheitsschädliche Arbeitsstoffe , 44. Lieferung, Ausgabe 2008 Der Artikel enthält folgende Kapitel: Allgemeiner Wirkungscharakter Wirkungsmechanismus Toxikokinetik und Metabolismus Aufnahme, Verteilung, Ausscheidung Metabolismus Erfahrungen beim Menschen Einmalige Exposition Wiederholte Exposition Wirkung auf Haut und Schleimhäute Allergene Wirkung Reproduktionstoxizität Genotoxizität Kanzerogenität Tierexperimentelle Befunde und In‐vitro‐Untersuchungen Akute Toxizität Subakute, subchronische und chronische Toxizität Wirkung auf Haut und Schleimhäute Allergene Wirkung Reproduktionstoxizität Genotoxizität Kanzerogenität Sonstige Wirkungen Bewertung Anhang

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Aminopyrine and biphenyl metabolism in cultured hepatocytes

Cited by 9 publications

References 15 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

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

Pentanol‐Isomeren [MAK Value Documentation in German language, 2008]

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