Relative expression of cytochrome P450 isoenzymes in human liver and association with the metabolism of drugs and xenobiotics

Lesley M. Forrester, Colin Henderson, Michael J. Glancey, David J. Back, B. Kevin Park, Simon E. Ball, Neil R. Kitteringham, Aileen W. McLaren, John S. Miles, Paul Skett, C. Roland Wolf

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    Abstract

    Cytochrome P450s play a central role in the metabolism and disposition of an extremely wide range of drugs and chemical carcinogens. Individual differences in the expression of these enzymes may be an important determinant in susceptibility to adverse drug reactions, chemical toxins and mutagens. In this paper, we have measured the relative levels of expression of cytochrome P450 isoenzymes from eight gene families in a panel of twelve human liver samples in order to determine the individuality in their expression and whether any forms are co-regulated. Isoenzymes were identified in most cases on Western blots based on the mobility of authentic recombinant human cytochrome P450 standards. The levels of the following P450 proteins correlated with each other: CYP2A6, CYP2B6 and a protein from the CYP2C gene subfamily, CYP2E1 and a member of the CYP2A gene subfamily, CYP2C8, CYP3A3/A4 and total cytochrome P450 content. Also, the levels of two proteins in the CYP4A gene subfamily were highly correlated. These correlations are consistent with the relative regulation of members of these gene families in rats or mice. In addition, the level of expression of specific isoenzymes has also been compared with the rate of metabolism of a panel of drugs, carcinogens and model P450 substrates. These latter studies demonstrate and confirm that the correlations obtained in this manner represent a powerful approach towards the assignment of the metabolism of substrates by specific human P450 isoenzymes.

    Original languageEnglish
    Pages (from-to)359-368
    Number of pages10
    JournalBiochemical Journal
    Volume281
    Issue number2
    Publication statusPublished - 15 Jan 1992

    Cite this

    Forrester, Lesley M. ; Henderson, Colin ; Glancey, Michael J. ; Back, David J. ; Park, B. Kevin ; Ball, Simon E. ; Kitteringham, Neil R. ; McLaren, Aileen W. ; Miles, John S. ; Skett, Paul ; Wolf, C. Roland. / Relative expression of cytochrome P450 isoenzymes in human liver and association with the metabolism of drugs and xenobiotics. In: Biochemical Journal. 1992 ; Vol. 281, No. 2. pp. 359-368.
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    abstract = "Cytochrome P450s play a central role in the metabolism and disposition of an extremely wide range of drugs and chemical carcinogens. Individual differences in the expression of these enzymes may be an important determinant in susceptibility to adverse drug reactions, chemical toxins and mutagens. In this paper, we have measured the relative levels of expression of cytochrome P450 isoenzymes from eight gene families in a panel of twelve human liver samples in order to determine the individuality in their expression and whether any forms are co-regulated. Isoenzymes were identified in most cases on Western blots based on the mobility of authentic recombinant human cytochrome P450 standards. The levels of the following P450 proteins correlated with each other: CYP2A6, CYP2B6 and a protein from the CYP2C gene subfamily, CYP2E1 and a member of the CYP2A gene subfamily, CYP2C8, CYP3A3/A4 and total cytochrome P450 content. Also, the levels of two proteins in the CYP4A gene subfamily were highly correlated. These correlations are consistent with the relative regulation of members of these gene families in rats or mice. In addition, the level of expression of specific isoenzymes has also been compared with the rate of metabolism of a panel of drugs, carcinogens and model P450 substrates. These latter studies demonstrate and confirm that the correlations obtained in this manner represent a powerful approach towards the assignment of the metabolism of substrates by specific human P450 isoenzymes.",
    author = "Forrester, {Lesley M.} and Colin Henderson and Glancey, {Michael J.} and Back, {David J.} and Park, {B. Kevin} and Ball, {Simon E.} and Kitteringham, {Neil R.} and McLaren, {Aileen W.} and Miles, {John S.} and Paul Skett and Wolf, {C. Roland}",
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    Forrester, LM, Henderson, C, Glancey, MJ, Back, DJ, Park, BK, Ball, SE, Kitteringham, NR, McLaren, AW, Miles, JS, Skett, P & Wolf, CR 1992, 'Relative expression of cytochrome P450 isoenzymes in human liver and association with the metabolism of drugs and xenobiotics', Biochemical Journal, vol. 281, no. 2, pp. 359-368.

    Relative expression of cytochrome P450 isoenzymes in human liver and association with the metabolism of drugs and xenobiotics. / Forrester, Lesley M.; Henderson, Colin; Glancey, Michael J.; Back, David J.; Park, B. Kevin; Ball, Simon E.; Kitteringham, Neil R.; McLaren, Aileen W.; Miles, John S.; Skett, Paul; Wolf, C. Roland.

    In: Biochemical Journal, Vol. 281, No. 2, 15.01.1992, p. 359-368.

    Research output: Contribution to journalArticle

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    AU - Forrester, Lesley M.

    AU - Henderson, Colin

    AU - Glancey, Michael J.

    AU - Back, David J.

    AU - Park, B. Kevin

    AU - Ball, Simon E.

    AU - Kitteringham, Neil R.

    AU - McLaren, Aileen W.

    AU - Miles, John S.

    AU - Skett, Paul

    AU - Wolf, C. Roland

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    AB - Cytochrome P450s play a central role in the metabolism and disposition of an extremely wide range of drugs and chemical carcinogens. Individual differences in the expression of these enzymes may be an important determinant in susceptibility to adverse drug reactions, chemical toxins and mutagens. In this paper, we have measured the relative levels of expression of cytochrome P450 isoenzymes from eight gene families in a panel of twelve human liver samples in order to determine the individuality in their expression and whether any forms are co-regulated. Isoenzymes were identified in most cases on Western blots based on the mobility of authentic recombinant human cytochrome P450 standards. The levels of the following P450 proteins correlated with each other: CYP2A6, CYP2B6 and a protein from the CYP2C gene subfamily, CYP2E1 and a member of the CYP2A gene subfamily, CYP2C8, CYP3A3/A4 and total cytochrome P450 content. Also, the levels of two proteins in the CYP4A gene subfamily were highly correlated. These correlations are consistent with the relative regulation of members of these gene families in rats or mice. In addition, the level of expression of specific isoenzymes has also been compared with the rate of metabolism of a panel of drugs, carcinogens and model P450 substrates. These latter studies demonstrate and confirm that the correlations obtained in this manner represent a powerful approach towards the assignment of the metabolism of substrates by specific human P450 isoenzymes.

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    VL - 281

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    JO - Biochemical Journal

    JF - Biochemical Journal

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