The localization of cytochrome P-450 in normal and pathological human liver by monoclonal antibodies to human cytochrome P-450

1987 ◽  
Vol 15 (4) ◽  
pp. 677-678 ◽  
Author(s):  
G. I. MURRAY ◽  
T. S. BARNES ◽  
S. W. B. EWEN ◽  
H. F. SEWELL ◽  
W. T. MELVIN ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Human Liver ◽  
Human Cytochrome ◽  
Cytochrome P 450

scholarly journals Monoclonal antibodies against human cytochrome P-450 recognizing different pregnenolone 16α-carbonitrile-inducible rat cytochromes P-450

1987 ◽  
Vol 248 (1) ◽  
pp. 301-304 ◽  
Author(s):  
T S Barnes ◽  
P M Shaw ◽  
M D Burke ◽  
W T Melvin
Keyword(s):  
Monoclonal Antibodies ◽  
Human Liver ◽  
Liver Microsomes ◽  
Human Liver Microsomes ◽  
The Other ◽  
Male Rat ◽  
Rat Liver Microsomes ◽  
Human Cytochrome ◽  
Male Specific ◽  
Cytochrome P 450

Six murine monoclonal antibodies against human hepatic cytochrome P-450 have been raised, using human liver microsomes (microsomal fractions) or semi-purified human cytochrome P-450 as immunogen. All six antibodies recognized the same highly purified of human liver cytochrome P-450 of molecular mass 53 kDa and gave rise to a single band at 53 kDa on immunoblots of human liver microsomes from 11 individuals. The antibodies also recognized proteins at 52 kDa and 54 kDa on immunoblots of control and induced male-rat liver microsomes, showing four different banding patterns. Antibodies HL4 and HP16 recognized a 52 kDa protein that was only weakly expressed in untreated rats and which was strongly induced by pregnenolone 16 alpha-carbonitrile (PCN) but not by phenobarbitone (PB), 3-methylcholanthrene (3MC), isosafrole (ISF), Aroclor 1254 (ARO), clofibrate or imidazole. HP10 and HL5 recognized a constitutive 52 kDa protein that was weakly induced by PCN but not by the other agents and was suppressed by 3MC and ARO. HP3 recognized a 54 kDa protein that was undetectable in control rats but was strongly induced by PB, PCN, ISF and ARO. HL3 appeared to recognize a combination of the proteins recognized by the other antibodies plus a 54 kDa protein that was weakly expressed in control rats. The constitutive proteins recognized were male-specific.

Inhibitory monoclonal antibodies to human cytochrome P450 1A2: analysis of phenacetin O-deethylation in human liver

1998 ◽  
Vol 8 (5) ◽  
pp. 375-382 ◽  
Author(s):  
Tian J. Yang ◽  
Yang Sai ◽  
Kristopher W. Krausz ◽  
Frank J. Gonzalez ◽  
Harry V. Gelboin
Keyword(s):  
Cytochrome P450 ◽  
Monoclonal Antibodies ◽  
Human Liver ◽  
Cytochrome P450 1A2 ◽  
Human Cytochrome

Monoclonal antibodies against human liver cytochrome P-450

1985 ◽  
Vol 34 (19) ◽  
pp. 3547-3552 ◽  
Author(s):  
Philippe Beaune ◽  
Pierre Kremers ◽  
Francine Letawe-Goujon ◽  
Jacques E. Gielen
Keyword(s):  
Monoclonal Antibodies ◽  
Human Liver ◽  
Liver Cytochrome ◽  
Cytochrome P 450

scholarly journals Differences in the cytochrome P-450 isoenzymes involved in the 2-hydroxylation of oestradiol and 17 α-ethinyloestradiol. Relative activities of rat and human liver enzymes

1990 ◽  
Vol 267 (1) ◽  
pp. 221-226 ◽  
Author(s):  
S E Ball ◽  
L M Forrester ◽  
C R Wolf ◽  
D J Back
Keyword(s):  
Gene Family ◽  
Human Liver ◽  
Liver Enzymes ◽  
Important Determinant ◽  
Biological Effects ◽  
Gene Families ◽  
Liver Cytochrome ◽  
Human Cytochrome ◽  
Cytochrome P 450 ◽  
Gene Subfamily

The metabolism of oestradiol and 17 alpha-ethinyloestradiol to their 2-hydroxy derivatives is an important determinant in their biological effects. In this work, we have investigated which rat or human cytochrome P-450 isoenzymes are involved in catalysing these reactions. Oestradiol 2-hydroxylation was catalysed by a wide variety of rat cytochrome P-450s from gene families P450IA, P450IIB, P450IIC and P450IIIA. Interestingly, 17 alpha-ethinyloestradiol, which only differs structurally from oestradiol at a position distant from the site of oxidation, was metabolized predominantly by members of the P450IIC gene subfamily. In order to establish which enzymes are responsible for the oxidation of these substrates in man, antibodies to rat liver cytochrome P-450 isoenzymes were used to inhibit these reactions in a panel of human liver microsomal fractions. Also, possible correlations between the proteins recognized by the antibodies and the 2-hydroxylation rate were determined. These experiments provide evidence that 2-hydroxylation of 17 alpha-ethinyloestradiol in man is catalysed by cytochromes from the P450IIC, P450IIE and P450IIIA gene families. In contrast, the major proteins involved in oestradiol metabolism are from the P450IA gene family, although members of the P450IIC and P450IIE gene families may also play a role. These data demonstrate that the differences in the capacity of rat P-450s to metabolize these substrates are also present in the comparable enzymes involved in man, and that a variety of factors will determine the rate of disposition of these compounds in man.

scholarly journals Differences in adult and foetal human cytochrome P-450 forms recognized by monoclonal antibodies with specificity for the P450III family

1989 ◽  
Vol 260 (3) ◽  
pp. 635-640 ◽  
Author(s):  
T S Barnes ◽  
M D Burke ◽  
W T Melvin
Keyword(s):  
Monoclonal Antibodies ◽  
Polyacrylamide Gel Electrophoresis ◽  
Liver Microsomes ◽  
Covalent Modification ◽  
Adult Liver ◽  
Human Adult ◽  
Human Cytochrome ◽  
Foetal Liver ◽  
Cytochrome P 450 ◽  
Murine Monoclonal Antibodies

Six murine monoclonal antibodies raised against a major human adult liver cytochrome P-450 (P-450) of the PCN family (P450III) detected a protein in human foetal liver microsomes (microsomal fractions) which had an approx. 1 kDa higher molecular mass on SDS/polyacrylamide-gel electrophoresis than the protein recognized in human adult liver microsomes. Although each of the antibodies recognized both the adult and the foetal forms, antibody HL4 showed higher affinity for the foetal form. Recognition by the monoclonal antibodies of peptides generated by proteolytic cleavage of microsomal proteins showed different patterns for the adult and foetal forms. It is concluded that the foetal P-450 form recognized by antibodies to the major human adult liver form P450hA7, although structurally similar, is either a distinct P-450 isoenzyme or that the adult and foetal proteins have different covalent modification. Immunoquantification experiments showed comparable levels of the P-450 forms in adult and foetal liver, although there appeared to be less inter-individual variation in foetal livers.

Metabolism of rifabutin and its 25-desacetyl metabolite, LM565, by human liver microsomes and recombinant human cytochrome P-450 3A4: relevance to clinical interaction with fluconazole.

1997 ◽  
Vol 41 (5) ◽  
pp. 924-926 ◽  
Author(s):  
C B Trapnell ◽  
C Jamis-Dow ◽  
R W Klecker ◽  
J M Collins
Keyword(s):  
Human Liver ◽  
High Performance ◽  
Opportunistic Infections ◽  
Liver Microsomes ◽  
Human Liver Microsomes ◽  
Hepatic Enzymes ◽  
Microsomal Enzymes ◽  
Human Cytochrome ◽  
Immunodeficiency Virus ◽  
Cytochrome P 450

Rifabutin and fluconazole are often given concomitantly as therapy to prevent opportunistic infections in individuals infected with the human immunodeficiency virus. Recent reports have shown increased levels of rifabutin and its 25-desacetyl metabolite, LM565, in plasma when rifabutin is administered with fluconazole. Since fluconazole is known to inhibit microsomal enzymes, this study was undertaken to determine if this rifabutin-fluconazole interaction was due to an inhibition of human hepatic enzymes. The metabolism of both rifabutin and LM565 was evaluated in human liver microsomes and recombinant human cytochrome P-450 (CYP) 3A4 in the presence of fluconazole and other probe drugs known to inhibit CYP groups 1A2, 2C9, 2D6, 2E1, and 3A. The concentrations of rifabutin (1 microg/ml), LM565 (1 microg/ml), and fluconazole (10 and 100 microg/ml) used were equal to those observed in plasma after the administration of rifabutin and fluconazole at clinically relevant doses. High-performance liquid chromatography was used to assess the metabolism of rifabutin and LM565. Rifabutin was readily metabolized to LM565 by human microsomes, but the reaction was independent of NADPH and was not affected by the P-450 inhibitors. No rifabutin metabolism by recombinant CYP 3A4 was found to occur. LM565 was also metabolized by human microsomes to two products, but metabolism was dependent on NADPH and was affected by certain P-450 inhibitors. In addition, LM565 was readily metabolized by the recombinant CYP 3A4 to the same two products found with its metabolism by human microsomes. Therefore, rifabutin is metabolized by human microsomes but not via cytochrome P-450 enzymes, whereas LM565 is metabolized by CYP 3A4.

A human cytochrome P-450 characterized by inhibition studies as the sparteine–debrisoquine monooxygenase

1984 ◽  
Vol 62 (7) ◽  
pp. 860-862 ◽  
Author(s):  
T. Inaba ◽  
M. Nakano ◽  
S. V. Otton ◽  
W. A. Mahon ◽  
W. Kalow
Keyword(s):  
Correlation Coefficient ◽  
Human Liver ◽  
Liver Microsomes ◽  
Human Liver Microsomes ◽  
Human Cytochrome ◽  
Competitive Inhibitors ◽  
Inhibition Constants ◽  
Inhibition Studies ◽  
Cytochrome P 450

The present study compares the debrisoquine monooxygenase and the sparteine monooxygenase activities of human liver microsomes. In the presence of 14 competitive inhibitors, apparent inhibition constants (Ki) as determined by these two activities ranged over four orders of magnitude with a correlation coefficient 0.99. These in vitro results represent the strongest evidence to date that the debrisoquine monooxygenase and the sparteine monooxygenase are identical and involve a single isozyme of cytochrome P-450.

Monoclonal antibodies against human cytochrome P-450

1986 ◽  
Vol 14 (3) ◽  
pp. 621-621 ◽  
Author(s):  
TRISTAN S. BARNES ◽  
PETER M. SHAW ◽  
M. DANNY BURKE ◽  
WILLIAM T. MELVIN
Keyword(s):  
Monoclonal Antibodies ◽  
Human Cytochrome ◽  
Cytochrome P 450
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