In Vitro and in Vivo Drug Interactions Involving Human Cyp3a

Thummel, Kenneth E.; Wilkinson, Grant R.

doi:10.1146/annurev.pharmtox.38.1.389

Cited by 761 publications

(533 citation statements)

References 215 publications

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“…[55][56][57][58] Expression of these enzymes has been shown to decrease upon the isolation of hepatocytes from the liver. 57,58 The gene set MONOOXYGENASE_ACTIVITY contains several cytochrome P450 genes and flavin containing monooxygenase.…”

Section: Monooxygenases Are Initially Not Differentially Expressed Bumentioning

confidence: 99%

A Comparative Study of Genome-Wide Transcriptional Profiles of Primary Hepatocytes in Collagen Sandwich and Monolayer Cultures

Kim

Lasher

Milford

et al. 2010

Tissue Engineering Part C: Methods

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Two commonly used culture systems in hepatic tissue engineering are the collagen sandwich (CS) and monolayers of cells. In this study, genome-wide gene expression profiles of primary hepatocytes were measured over an 8-day period for each cell culture system using Affymetrix GeneChips and compared via gene set enrichment analysis to elicit biologically meaningful information at the level of gene sets. Our results demonstrate that gene expression in hepatocytes in CS cultures steadily and comprehensively diverges from that in monolayer cultures. Gene sets up-regulated in CS cultures include several associated with liver metabolic and synthesis functions, such as metabolism of lipids, amino acids, carbohydrates, and alcohol, and synthesis of bile acids. Monooxygenases such as Cytochrome-P450 enzymes do not show any change between the culture systems after 1 day, but exhibit significant up-regulation in CS cultures after 3 days in comparison to hepatocyte monolayers. These data provide insights into the up-and down-regulation of several liver-critical gene sets and their subsequent effects on liver-specific functions. These results provide a baseline for further explorations into the systems biology of engineered liver mimics.

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Section: Monooxygenases Are Initially Not Differentially Expressed Bumentioning

confidence: 99%

A Comparative Study of Genome-Wide Transcriptional Profiles of Primary Hepatocytes in Collagen Sandwich and Monolayer Cultures

Kim

Lasher

Milford

et al. 2010

Tissue Engineering Part C: Methods

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“…To study how promiscuity varies across members of this class of enzymes, we focus on three CYP isoforms that play important roles in phase I drug metabolism in humans: CYP2C9, CYP2C19, and CYP3A4. Together they comprise the majority of CYP content in the liver (45) and small intestine (46), and CYP3A4 alone is estimated to be responsible for the metabolism of more than 50% of the drugs on the market (47). Figure 3a contains the structures of each CYP substrate in the set, and Figure 3b shows the distribution of CYP substrates in chemical space (calculated using the same 92-bit keyset and algorithm described above).…”

Section: Proteasesmentioning

confidence: 99%

A Quantitative Index of Substrate Promiscuity

2007

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Catalytic promiscuity is a widespread, but poorly understood, phenomenon among enzymes with particular relevance to the evolution of new functions, drug metabolism, and in vitro biocatalyst engineering. However, there is at present no way to quantitatively measure or compare this important parameter of enzyme function. Here we define a quantitative index of promiscuity (I) that can be calculated from the catalytic efficiencies of an enzyme toward a defined set of substrates. A weighted promiscuity index (J) that accounts for patterns of similarity and dissimilarity among the substrates in the set is also defined. Promiscuity indices were calculated for three different enzyme classes: eight serine and cysteine proteases, two glutathione S-transferase (GST) isoforms, and three cytochrome P450 (CYP) isoforms. The proteases ranged from completely specific (granzyme B, J ) 0.00) to highly promiscuous (cruzain, J ) 0.83). The four drug-metabolizing enzymes studied (GST A1-1 and the CYP isoforms) were highly promiscuous, with J values between 0.72 and 0.92; GST A4-4, involved in the clearance of lipid peroxidation products, is moderately promiscuous (J ) 0.37). Promiscuity indices also allowed for studies of correlation between substrate promiscuity and an enzyme's activity toward its most-favored substrate, for each of the three enzyme classes.

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“…For this reason, several studies have focused on cytochromes P450 3A (CYP3As) polymorphisms, the rationale being that, in addition to the prominent role of CYP3A enzymes in the metabolism of over 50% of all clinical drugs (Li et al 1995, Thummel & Wilkinson 1998, Rodriguez-Antona & Ingelman-Sundberg 2006, CYP3A enzymes also metabolize testosterone and dehydroepiandrosterone (DHEA) to hydroxy-metabolitesless active and easier to eliminate (Ohmori et al 1998, Kamdem et al 2004, Miller et al 2004. Thus, an alteration in the CYP3A prostate activity could change the local testosterone levels and alter the tissue-specific androgen effects, prostate growth, and cancer development.…”

Section: Introductionmentioning

confidence: 99%

Cytochrome P450 3A5 is highly expressed in normal prostate cells but absent in prostate cancer

Leskelä

Honrado²,

Montero‐Conde

et al. 2007

Endocr Relat Cancer

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Testosterone is essential for the growth and function of the luminal prostate cells, but it is also critical for the development of prostate cancer, which in the majority of the cases derives from luminal cells. Cytochrome P450 3A (CYP3A) enzymes hydroxylate testosterone and dehydroepiandrosterone to less active metabolites, which might be the basis for the association between CYP3A polymorphisms and prostate cancer. However, it is unknown whether the CYP3A enzymes are expressed at relevant levels in the prostate and which polymorphisms could affect this tissue-specific CYP3A activity. Thus, we measured CYP3A4, CYP3A5, CYP3A7, and CYP3A43 mRNA in 14 benign prostatic hyperplasias and ten matched non-tumoral/tumoral prostate samples. We found that CYP3A5 mRNA in non-tumoral prostate tissue was 10% of the average amount of liver samples, whereas the expression of the other CYP3A genes was much lower. Similarly to liver, CYP3A5*3 polymorphism decreased CYP3A5 mRNA content 13-fold. CYP3A5 protein was detected in non-tumoral prostate microsomes by western blot, and immunohistochemistry (IHC) localized CYP3A5 exclusively in the basolateral prostate cells. In contrast to the normal tissue, IHC and RT-PCR showed that tumoral tissue lacked CYP3A5 expression. In conclusion, prostate basolateral cells express high levels of CYP3A5 which dramatically decrease in tumoral tissue. This finding supports an endogenous function of CYP3A5 related to the metabolism of intra-prostatic androgens and cell growth, and that polymorphisms affecting CYP3A5 activity may result in altered prostate cancer risk and aggressiveness.

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In Vitro and in Vivo Drug Interactions Involving Human Cyp3a

Cited by 761 publications

References 215 publications

A Comparative Study of Genome-Wide Transcriptional Profiles of Primary Hepatocytes in Collagen Sandwich and Monolayer Cultures

A Comparative Study of Genome-Wide Transcriptional Profiles of Primary Hepatocytes in Collagen Sandwich and Monolayer Cultures

A Quantitative Index of Substrate Promiscuity

Cytochrome P450 3A5 is highly expressed in normal prostate cells but absent in prostate cancer

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