REGULATION OF LIVER HEME METABOLISM & CYTOCHROME P 450 INACTIVATION

肝脏血红素代谢的调节

基本信息

项目摘要

The hepatic microsomal hemoproteins cytochromes P450 (P450) include multiple constitutive and inducible enzymes. These monomeric hemoproteins (MW @ 50kDa) contain one prosthetic heme (iron-protoporphyrin IX) moiety/mole of enzyme. In spite of their identical heme moieties, P450s differ functionally, a property conferred by individual heme-apocytochrome microenvironments. P450s are instrumental in the oxidative/reductive metabolism of various physiologically relevant endobiotics and xenobiotics. However, although all these reactions result in the formation of readily excretable products, not all are beneficial. P450s catalyze the metabolism of some substrates to radicals and other reactive species that can induce toxicity/pathological damage. Furthermore, in the course of certain redox reactions, the participating P450 is sacrificed in a process classified as a mechanism-based or "suicide" inactivation. To date, three distinct mechanisms of substrate-mediated P450 inactivation have been characterized: (a) prosthetic heme destruction via N-alkyl/arylation [i.e., allylisopropylacetamide (AIA), secobarbita (SB)I; (b) apocytochrome alkylatin by a reactive intermediate (chloramphenicol, SB, 11-undecynoic acid); and (c) destruction of the prosthetic heme to products that irreversibly bind to the apocytochrome [CC14,spironolactone (SPL), 3,5-dicarbethoxy-2,6-dimethyl-4-ethyl-1,4-dihydropyridine (DDEP)I. By definition, "suicide" inactivations occur at the active site. Isolation and structural characterization of the N-alkylated heme has unequivocally established this criterion for N-alkylation of P450 heme. However, the criterion for "suicide inactivation" has not been rigorously applied to modes b or c of drug-induced P450 destruction because the inaccessibility to structural analyses of the highly hydrophobic apoP450 active site regions and their resistance to proteolytic digestion (with an array of proteases) have until now largely precluded their definitive mechanistic classification. Using lysyl endopeptidase C and/or pepsin digestion as well as CNBr cleavage, the P450 peptides modified by either the heme or the drug have been HPLC mapped and isolated as a first step to their identification and structural characterization by mass spectrometric analyses using an array of mass spectrometric techniques provided by the Mass Spectrometry Facility. To date, two different P450 peptides alkylated by heme and SB have been isolated and characterized, using ESMS and MSLDIMS. Such structural characterization will greatly contribute to the definitive mechanistic elucidation of modes b and c inactivation processes.
肝微粒体血红蛋白P450 (P450)

项目成果

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Maria Almira Correia其他文献

Maria Almira Correia的其他文献

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{{ truncateString('Maria Almira Correia', 18)}}的其他基金

REGULATION OF LIVER CYTOCHROME P450 TURNOVER/HEPATIC DEGRADATION OF P450 ENZYMES
肝细胞色素 P450 周转/P450 酶的肝脏降解的调节
  • 批准号:
    8363745
  • 财政年份:
    2011
  • 资助金额:
    $ 1.44万
  • 项目类别:
REGULATION OF LIVER CYTOCHROME P450 TURNOVER/HEPATIC DEGRADATION OF P450 ENZYMES
肝细胞色素 P450 周转/P450 酶的肝脏降解的调节
  • 批准号:
    8169738
  • 财政年份:
    2010
  • 资助金额:
    $ 1.44万
  • 项目类别:
REGULATION OF LIVER HEME METABOLISM AND CYTOCHROME P-450
肝脏血红素代谢和细胞色素 P-450 的调节
  • 批准号:
    7957375
  • 财政年份:
    2009
  • 资助金额:
    $ 1.44万
  • 项目类别:
REGULATION OF LIVER HEME METABOLISM AND CYTOCHROME P-450
肝脏血红素代谢和细胞色素 P-450 的调节
  • 批准号:
    7724178
  • 财政年份:
    2008
  • 资助金额:
    $ 1.44万
  • 项目类别:
REGULATION OF LIVER HEME METABOLISM AND CYTOCHROME P-450
肝脏血红素代谢和细胞色素 P-450 的调节
  • 批准号:
    7601826
  • 财政年份:
    2007
  • 资助金额:
    $ 1.44万
  • 项目类别:
REGULATION OF LIVER HEME METABOLISM AND CYTOCHROME P-450 INACTIVATION/HEPATIC D
肝脏血红素代谢和细胞色素 P-450 失活/肝 D 的调节
  • 批准号:
    7369058
  • 财政年份:
    2006
  • 资助金额:
    $ 1.44万
  • 项目类别:
REGULATION OF LIVER HEME METABOLISM AND CYTOCHROME P-450 INACTIVATION/HEPATIC D
肝脏血红素代谢和细胞色素 P-450 失活/肝 D 的调节
  • 批准号:
    7180959
  • 财政年份:
    2005
  • 资助金额:
    $ 1.44万
  • 项目类别:
REGULATION OF LIVER HEME METABOLISM AND CYTOCHROME P-450 INACTIVATION/HEPATIC DE
肝脏血红素代谢和细胞色素 P-450 失活/肝 DE 的调节
  • 批准号:
    6976650
  • 财政年份:
    2004
  • 资助金额:
    $ 1.44万
  • 项目类别:
REGULATION OF LIVER HEME METABOLISM & CYTOCHROME P 450 INACTIVATION
肝脏血红素代谢的调节
  • 批准号:
    6308799
  • 财政年份:
    2000
  • 资助金额:
    $ 1.44万
  • 项目类别:
REGULATION OF LIVER HEME METABOLISM & CYTOCHROME P 450 INACTIVATION
肝脏血红素代谢的调节
  • 批准号:
    6281153
  • 财政年份:
    1998
  • 资助金额:
    $ 1.44万
  • 项目类别:

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