Limited contribution of CYP3A5 to the hepatic 6?-hydroxylation of testosterone

Kamdem, Landry K.; Meineke, Ingolf; Koch, Ina; Zanger, Ulrich M.; Brockmöller, Jürgen; Wojnowski, Leszek

doi:10.1007/s00210-004-0944-3

Cited by 16 publications

(11 citation statements)

References 22 publications

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“…The contribution of CYP3A5 to the 13-O-demethylation of tacrolimus in HLMs varied from 1.5% to 40% and was particularly strong in livers with low CYP3A4, whereas it was lower in those with high CYP3A4 and in the 3 CYP3A5 low expressers. These findings support the observations that CYP3A5 is an important source of interindividual variability for CYP3A when CYP3A5 content represents a significant fraction of the total hepatic CYP3A pool (36,38,41 ). Conversely, the share of CYP3A5 in tacrolimus metabolism undergoes "dilution" in individuals with high concentrations of CYP3A4.…”

Section: Discussionsupporting

confidence: 88%

“…2 of the online Data Supplement) between V max values for tacrolimus 13-O-demethylation and those for testosterone 6␤-hydroxylation (supplied in the package insert for each HLM). Because the latter reaction is a marker of CYP3A activity (36 ), this result further confirms that tacrolimus is mostly metabolized by CYP3A. The data in Fig.…”

Section: Tacrolimus Metabolism By Baculovirusexpressed Cytochrome P450supporting

confidence: 77%

“…The predominant role of CYP3A isoforms in the 13-O-demethylation of tacrolimus is in agreement with the good correlation observed between tacrolimus 13-O-demethylation activity and 6␤-hydroxylation of testosterone in the liver samples investigated. The latter is widely used as a marker of CYP3A activity (36,42 ).…”

Section: Discussionmentioning

confidence: 99%

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Contribution of CYP3A5 to the in Vitro Hepatic Clearance of Tacrolimus

et al. 2005

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Background: Tacrolimus is metabolized predominantly to 13-O-demethyltacrolimus in the liver and intestine by cytochrome P450 3A (CYP3A). Patients with high concentrations of CYP3A5, a CYP3A isoenzyme polymorphically produced in these organs, require higher doses of tacrolimus, but the exact mechanism of this association is unknown. Methods: cDNA-expressed CYP3A enzymes and a bank of human liver microsomes with known CYP3A4 and CYP3A5 content were used to investigate the contribution of CYP3A5 to the metabolism of tacrolimus to 13-O-demethyltacrolimus as quantified by liquid chromatography-tandem mass spectrometry. Results: Demethylation of tacrolimus to 13-O-demethyltacrolimus was the predominant clearance reaction. Calculated K m and V max values for CYP3A4, CYP3A5, and CYP3A7 cDNA-expressed microsomes were 1.5 mol/L and 0.72 pmol ⅐ (pmol P450) ؊1 ⅐ min ؊1 , 1.4 mol/L and 1.1 pmol ⅐ (pmol P450) ؊1 ⅐ min ؊1 , and 6 mol/L and 0.084 pmol ⅐ (pmol P450) ؊1 ⅐ min ؊1 , respectively. Recombinant CYP3A5 metabolized tacrolimus with a catalytic efficiency (V max /K m ) that was 64% higher than that of CYP3A4. The contribution of CYP3A5 to 13-O-demethylation of tacrolimus in human liver microsomes varied from 1.5% to 40% (median, 18.8%). There was an inverse association between the contribution of CYP3A5 to 13-O-demethylation and the amount of 3A4 protein (r ‫؍‬ 0.90; P <0.0001). Mean 13-O-demethylation clearances in CYP3A5 high and low expressers, estimated by the parallel-tube liver model,

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Section: Discussionsupporting

confidence: 88%

Section: Tacrolimus Metabolism By Baculovirusexpressed Cytochrome P450supporting

confidence: 77%

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Contribution of CYP3A5 to the in Vitro Hepatic Clearance of Tacrolimus

et al. 2005

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“…Although cytochrome b 5 was not uniformly present in all P450s tested, the use of two different microsomal systems (recombinant enzymes and a panel of well characterized human liver microsomes) predicts a major involvement of CYP3A and CYP1A in the primary metabolism of exemestane. Consistent with this conclusion, CYP3A and CYP1A have been shown to be involved in the metabolism of steroid-like compounds such as pregnenolone (Niwa et al, 1998), progesterone (Schwarz et al, 2000), estradiol (Ohe et al, (Kamdem et al, 2004), and estrone (Cribb et al, 2006). Furthermore, unpublished data provided by the prescribing manufacturer suggest that coadministration of ketoconazole (a potent CYP3A inhibitor) does not alter exemestane exposure in humans.…”

Section: Discussionmentioning

confidence: 78%

In Vitro Cytochrome P450-Mediated Metabolism of Exemestane

2010

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ABSTRACT:Exemestane is a potent and irreversible steroidal aromatase inhibitor drug used for the treatment of estrogen receptor-positive breast cancer. Our aim was to identify and assess the contribution of the specific cytochromes P450 (P450s) responsible for exemestane primary in vitro metabolism. With the use of high-performance liquid chromatography and liquid chromatography-tandem mass spectrometry analytical techniques, 17-hydroexemestane (MI) formation and 6-hydroxymethylexemestane (MII) formation were found to be the predominant exemestane metabolic pathways. In a bank of 15 well characterized human liver microsomes with known P450 isoform-specific activities, the MI formation rate correlated significantly with CYP1A2 (Spearman r ‫؍‬ 0.60, p ‫؍‬ 0.02) and CYP4A11 (Spearman r ‫؍‬ 0.67, p ‫؍‬ 0.01) isoform-specific activities, whereas the MII production rate significantly correlated with CYP2B6 (Spearman r ‫؍‬ 0.57, p ‫؍‬ 0.03) and CYP3A (Spearman r ‫؍‬ 0.76, p ‫؍‬ 0.005) isoform-specific activities. Recombinant CYP1A1 metabolized exemestane to MI with a catalytic efficiency (Cl int ) of 150 nl/pmol P450 ؋ min that was at least 3.5-fold higher than those of other P450s investigated. Recombinant CYP3A4 catalyzed MII formation from exemestane with a catalytic efficiency of 840 nl/ pmol P450 ؋ min that was at least 4-fold higher than those of other P450s investigated. Among a panel of 10 chemical inhibitors tested, only ketoconazole and troleandomycin (CYP3A-specific chemical inhibitors) significantly inhibited the formation of MII by 45 and 95%, respectively. None of them markedly inhibited the formation of MI. In summary, exemestane seems to be metabolized to MI by multiple P450s that include CYP4A11 and CYP1A1/2, whereas its oxidation to MII is primarily mediated by CYP3A.

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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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Limited contribution of CYP3A5 to the hepatic 6?-hydroxylation of testosterone

Cited by 16 publications

References 22 publications

Contribution of CYP3A5 to the in Vitro Hepatic Clearance of Tacrolimus

Contribution of CYP3A5 to the in Vitro Hepatic Clearance of Tacrolimus

In Vitro Cytochrome P450-Mediated Metabolism of Exemestane

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

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