Effects of cytochrome b5 on drug oxidation activities of human cytochrome P450 (CYP) 3As: similarity of CYP3A5 with CYP3A4 but not CYP3A7

Yamaori, Satoshi; Yamazaki, Hiroshi; Suzuki, Akihiro; Yamada, Ayako; Tani, Hirofumi; Kamidate, Tamio; Fujita, Ken‐ichi; Kamataki, Tetsuya

doi:10.1016/j.bcp.2003.08.004

Cited by 51 publications

(100 citation statements)

References 49 publications

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“…2), consistent with previously reported values of 2.4 to 12 M for liver microsomes (Gascon and Dayer, 1991;Sharer et al, 1995;Ghosal et al, 1996; Transon et al, 1996;Von Moltke et al, 1996b;Maenpaa et al, 1998;Wandel et al, 1998;Wang et al, 1999;Martinez et al, 2000;Warrington et al, 2000;Yin et al, 2000;Hamaoka et al, 2001;Andrews et al, 2002;Li et al, 2003) (Fig. 4), 1.0 to 8.9 M for rCYP3A4 (Ghosal et al, 1996;Gibbs et al, 1999;Eiselt et al, 2001;Khan et al, 2002;Obach and Reed-Hagen, 2002;Williams et al, 2002;Yamaori et al, 2003), and 4.1 to 14 M for rCYP3A5 (Gibbs et al, 1999;Williams et al, 2002;Yamaori et al, 2003). Testosterone 6␤-hydroxylase is a very well established CYP3A marker activity.…”

Section: Validated Assays For Human Cytochrome P450 Enzymessupporting

confidence: 81%

Validated Assays for Human Cytochrome P450 Activities

Walsky

Obach²

2004

Drug Metab Dispos

468

380

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ABSTRACT:The measurement of the effect of new chemical entities on human cytochrome P450 marker activities using in vitro experimentation represents an important experimental approach in drug development. In vitro drug interaction data can be used in guiding the design of clinical drug interaction studies, or, when no effect is observed in vitro, the data can be used in place of an in vivo study to claim that no interaction will occur in vivo. To make such a claim, it must be assured that the in vitro experiments are performed with absolute confidence in the methods used and data obtained. To meet this need, 12 semiautomated assays for human P450 marker substrate activities have been developed and validated using approaches described in the GLP (good laboratory practices) as per the code of U.S. Federal Regulations. The assays that were validated are: phenacetin O-deethylase (CYP1A2), coumarin 7-hydroxylase (CYP2A6), bupropion hydroxylase (CYP2B6), amodiaquine N-deethylase (CYP2C8), diclofenac 4-hydroxylase and tolbutamide methylhydroxylase (CYP2C9), (S)-mephenytoin 4-hydroxylase (CYP2C19), dextromethorphan O-demethylase (CYP2D6), chlorzoxazone 6-hydroxylase (CYP2E1), felodipine dehydrogenase, testosterone 6␤-hydroxylase, and midazolam 1-hydroxylase (CYP3A4 and CYP3A5). High-pressure liquid chromatography-tandem mass spectrometry, using stable isotope-labeled internal standards, has been applied as the analytical method. This analytical approach, through its high sensitivity and selectivity, has permitted the use of very low incubation concentrations of microsomal protein (0.01-0.2 mg/ml). Analytical assay accuracy and precision values were excellent. Enzyme kinetic and inhibition parameters obtained using these methods demonstrated high precision and were within the range of values previously reported in the scientific literature. These methods should prove useful in the routine assessments of the potential for new drug candidates to elicit pharmacokinetic drug interactions via inhibition of cytochrome P450 activities.Drug-drug interactions are of great interest to scientists involved in drug research, regulatory authorities who are responsible for public safety, physicians, and their patients. Since "polypharmacy," or the practice of simultaneous prescription of more than one drug to treat one or more conditions in a single patient, has become a more common practice, drug interactions have been cited as one of the major reasons for hospitalization and even death (Lazarou et al., 1998). Thus, a great deal of effort is expended by researchers engaged in new drug research in avoiding the development of compounds that will cause drug-drug interactions.The most common mechanism underlying drug-drug interactions is the inhibition of cytochrome P450 activities. Several drugs in common use cause large increases in exposure to other drugs. Examples include ketoconazole, itraconazole, erythromycin, clarithromycin, diltiazem, and nefazodone (CYP3A); quinidine, paroxetine, and terbinafine (CYP2D6); ticlopidine (CYP2C19); ...

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Section: Validated Assays For Human Cytochrome P450 Enzymessupporting

confidence: 81%

Validated Assays for Human Cytochrome P450 Activities

Walsky

Obach²

2004

Drug Metab Dispos

468

380

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“…Cytochrome b 5 is mandatory and may stimulate or inhibit P450 enzymes depending on substrate and isoform. In CYP3A4 and CYP3A5, the presence of cytochrome b 5 increased V max values of midazolam 1Ј-hydroxylation (Yamaori et al, 2003). In our study, midazolam-1Ј-hydroxylation was activated in both rCYP3A4 and rCYP3A5 supplemented with cytochrome b 5 , whereas the stimulation was not observed in rCYP3A4 without cytochrome b 5 .…”

Section: Effect Of Efavirenz On the Midazolam 1ј-hydroxylation By Hlmcontrasting

confidence: 41%

Drug Interaction of Efavirenz and Midazolam: Efavirenz Activates the CYP3A-Mediated Midazolam 1′-Hydroxylation In Vitro

Keubler

Weiß²,

Haefeli³

et al. 2012

Drug Metab Dispos

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“…It has also been known for some time that the endoplasmic reticular cytochrome b 5 augments the activities of numerous CYPs (Lamb et al 2001, Yamazaki et al 2002, Yamaori et al 2003. A strong positive correlation between DHEA production and the significant co-localisation of cytochrome b 5 and CYP17 in the endoplasmic reticulum of the gonads and the zona reticularis of the adrenal cortex initially implicated the involvement of cytochrome b 5 as a potential modulator of the cleavage activity of CYP17 (Lu et al 1974(Lu et al , 1975.…”

Section: Cytochrome B 5 Modulates Cyp17 Activitymentioning

confidence: 99%

Cytochrome b5 modulation of 17α hydroxylase and 17–20 lyase (CYP17) activities in steroidogenesis

Akhtar¹,

Kelly²,

Kaderbhai³

2005

Journal of Endocrinology

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CYP17 is a steroidogenic enzyme located in the zona fasciculata and zona reticularis of the adrenal cortex and gonad tissues and which has dual functions -hydroxylation and as a lyase. The first activity gives hydroxylation of pregnenolone and progesterone at the C 17 position to generate 17 -hydroxypregnenolone and 17 -hydroxyprogesterone, while the second enzymic activity cleaves the C 17 -C 20 bond of 17 -hydroxypregnenolone and 17 -hydroxyprogesterone to form dehydroepiandrosterone and androstenedione respectively. The modulation of these two activities occurs through cytochrome b 5 . Association of cytochrome b 5 and CYP17 is thought to be based primarily on electrostatic interactions in which the negatively charged residues pair up with positively charged residues on the proximal surface of the CYP17 molecule. Non-specific interactions of the hydrophobic membrane regions of cytochrome b 5 and CYP17 are also thought to play a crucial role in the association of these two haemoproteins. Although cytochrome b 5 is known to stimulate CYP activity by contributing the second electron in the catalytic cycle, in the case of CYP17, the mechanism of cleavage stimulation proceeds via an allosteric mode. It is hypothesised that cytochrome b 5 promotes the cleavage by aligning the iron-oxygen complex attack onto the C 20 rather than the C 17 atom of the steroid substrate molecule. Thus, further understanding of the mechanism of modulation by cytochrome b 5 of the hydroxylase and lyase activities should shed new insights on developing therapeutic targets in CYP17-linked biochemical processes such as adrenarche, polycystic ovary syndrome and prostate cancer.

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Effects of cytochrome b5 on drug oxidation activities of human cytochrome P450 (CYP) 3As: similarity of CYP3A5 with CYP3A4 but not CYP3A7

Cited by 51 publications

References 49 publications

Validated Assays for Human Cytochrome P450 Activities

Validated Assays for Human Cytochrome P450 Activities

Drug Interaction of Efavirenz and Midazolam: Efavirenz Activates the CYP3A-Mediated Midazolam 1′-Hydroxylation In Vitro

Cytochrome b5 modulation of 17α hydroxylase and 17–20 lyase (CYP17) activities in steroidogenesis

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