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

1992 ◽  
Vol 281 (2) ◽  
pp. 359-368 ◽  
Author(s):  
L M Forrester ◽  
C J Henderson ◽  
M J Glancey ◽  
D J Back ◽  
B K Park ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Human Liver ◽  
Gene Families ◽  
Cytochrome P450s ◽  
Western Blots ◽  
Human Cytochrome ◽  
Wide Range ◽  
Powerful Approach ◽  
Highly Correlated ◽  
Gene Subfamily

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 or subfamilies 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.

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.

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

scholarly journals Determining the IC50 Values for Vorozole and Letrozole, on a Series of Human Liver Cytochrome P450s, to Help Determine the Binding Site of Vorozole in the Liver

2015 ◽  
Vol 2015 ◽  
pp. 1-4 ◽  
Author(s):  
Lendelle Raymond ◽  
Nikita Rayani ◽  
Grace Polson ◽  
Kylie Sikorski ◽  
Ailin Lian ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
High Throughput Screening ◽  
Human Liver ◽  
Potent Inhibitor ◽  
Cytochrome P450s ◽  
Third Generation ◽  
Weak Inhibitor ◽  
Liver Cytochrome ◽  
Ic50 Values ◽  
Screening Assays

Vorozole and letrozole are third-generation aromatase (cytochrome P450 19A1) inhibitors. [11C]-Vorozole can be used as a radiotracer for aromatase in living animals but when administered by IV, it collects in the liver. Pretreatment with letrozole does not affect the binding of vorozole in the liver. In search of finding the protein responsible for the accumulation of vorozole in the liver, fluorometric high-throughput screening assays were used to test the inhibitory capability of vorozole and letrozole on a series of liver cytochrome P450s (CYP1A1, CYP1A2, CYP2A6, and CYP3A4). It was determined that vorozole is a potent inhibitor of CYP1A1 (IC50 = 0.469 μM) and a moderate inhibitor of CYP2A6 and CYP3A4 (IC50 = 24.4 and 98.1 μM, resp.). Letrozole is only a moderate inhibitor of CYP1A1 and CYP2A6 (IC50 = 69.8 and 106 μM) and a very weak inhibitor of CYP3A4 (<10% inhibition at 1 mM). Since CYP3A4 makes up the majority of the CYP content found in the human liver, and vorozole inhibits it moderately well but letrozole does not, CYP3A4 is a good candidate for the protein that [11C]-vorozole is binding to in the liver.

Cytochrome P450 Monooxygenases and Interactions of Psychotropic Drugs: A Five-Year Update

1995 ◽  
Vol 25 (3) ◽  
pp. 277-290 ◽  
Author(s):  
Winston W. Shen
Keyword(s):  
Cytochrome P450 ◽  
Psychotropic Drugs ◽  
Selective Serotonin Reuptake Inhibitors ◽  
Gene Clusters ◽  
Serum Levels ◽  
Cytochrome P450s ◽  
Cytochrome P450 Monooxygenases ◽  
P450 Monooxygenases ◽  
Human Cytochrome ◽  
Enzymatic Induction

Objective: This article is a five-year update on a previous review article ( International Journal of Psychiatry in Medicine, 21:47–56, 1991) on cytochrome P450 monooxygenases and interactions of psychotropic drugs. Method: In the literature review, the recent committee work on nomenclature of the P450 superfamily are highlighted. Then, the author reviewed gene clusters of three human cytochrome P450s— CYP1A2, CYP2D6, and CYP3A4 with the focus on the changes of serum levels of the coadministered psychotropic drugs in the context of enzymatic induction and inhibition of these three hepatic enzymes. Results: As indicated in one table, the author stratified probes, inducers, inhibitors, chemical reactions, and substrates under these three gene clusters. As shown in another simple table, the author compared the hepatic enzymatic inhibitions of four selective serotonin reuptake inhibitors and pointed out the inhibition potentials of fluvoxamine at CYP1A2, fluoxetine and paroxetine at CYP2D6, and fluoxetine and fluvoxamine at CYP3A4 if these two SSRIs have higher serum concentrations. Conclusion: The author suggests that with these systematic approaches, this rapidly adding knowledge can help psychiatrists better understand psychotropic drug interactions and maximize the benefits of patients' psychopharmacotherapy.

STEREOSELECTIVE METABOLISM OF ENDOSULFAN BY HUMAN LIVER MICROSOMES AND HUMAN CYTOCHROME P450 ISOFORMS

2006 ◽  
Vol 34 (7) ◽  
pp. 1090-1095 ◽  
Author(s):  
Hwa-Kyung Lee ◽  
Joon-Kwan Moon ◽  
Chul-Hee Chang ◽  
Hoon Choi ◽  
Hee-Won Park ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Human Liver ◽  
Liver Microsomes ◽  
Human Liver Microsomes ◽  
Stereoselective Metabolism ◽  
Human Cytochrome ◽  
Cytochrome P450 Isoforms
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