Differential catalytic properties in metabolism of endogenous and exogenous substrates among CYP3A enzymes expressed in COS-7 cells

Ohmori, Shigeru; Nakasa, Hiromitsu; Asanome, Kazuki; Kurose, Yasusi; Ishii, Itsuko; Hosokawa, Masakiyo; Kitada, Munehiro

doi:10.1016/s0304-4165(97)00156-6

Cited by 66 publications

(34 citation statements)

References 33 publications

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“…The difference between the prostatic and hepatic CYP3A5 mRNA and protein contents could indicate a tissue-specific CYP3A5 posttranscriptional regulation. In any case, the high CYP3A5 prostatic expression suggests that CYP3A5 may play a relevant function in the prostate and, since the prostate is not a tissue relevant for drug metabolism, this function must be related to the metabolism of prostatic endogenous CYP3A5 substrates, such as androgens (Ohmori et al 1998, Miller et al 2004. In other tissues CYP3A5 has also been shown to play an important endogenous function, and CYP3A5*3 has been shown to influence the systolic blood and pulse pressure, presumably by altering CYP3A5-mediated glucocorticoid metabolism (Kreutz et al 2005).…”

Section: Discussionmentioning

confidence: 99%

“…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%

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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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Section: Discussionmentioning

confidence: 99%

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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“…Since DHEA-S activates CYP3A7-mediated CBZ 10,11-epoxidation, there is a possibility that DHEA-S affects drugmetabolism in fetuses and neonates period in vivo. Although only limited data exist about CYP3A7-mediated drug metabolism, the drug metabolism activity of CYP3A7 is generally lower than that of CYP3A4 in vitro (Ohmori et al, 1998;Williams et al, 2002). However, the results of an in vitro reaction system, which contains a single substrate and enzyme, may or may not reflect drug metabolism activity in vivo.…”

Section: Kinetic Parameters Of Dhea-s 16␣-hydroxylation By Expressed mentioning

confidence: 99%

“…For example, CYP3A4 catalyzes testosterone 6␤-hydroxylation with high activity, whereas CYP3A7 shows little of this activity. On the other hand, CYP3A7 catalyzes DHEA-S 16␣-hydroxylation with high activity, whereas CYP3A4 is mostly unreactive (Kitada et al, 1987;Ohmori et al, 1998). Although only limited data exist about CYP3A7-mediated drug metabolism, the drug metabolic activity of CYP3A7 seems, in general, to be lower than that of CYP3A4 (Ohmori et al, 1998;Williams et al, 2002).…”

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confidence: 99%

CYP3A4 and CYP3A7-Mediated Carbamazepine 10,11-Epoxidation Are Activated by Differential Endogenous Steroids

Nakamura

Torimoto

Ishii

et al. 2003

Drug Metabolism and Disposition

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This article is available online at http://dmd.aspetjournals.org ABSTRACT:Recently, we reported that several endogenous steroids affect CYP3A4-mediated drug metabolism, using human adult liver microsomes as an enzyme source. Especially, carbamazepine (CBZ) 10,11-epoxidation is activated by androstenedione (AND). In the present studies, we investigated the effects of endogenous steroids on the activity of CBZ 10,11-epoxidation by expressed CYP3A4 and CYP3A7. When expressed CYP3A4 was used as an enzyme source, the addition of AND to the reaction mixture also caused a drastic increase in the activity of CBZ 10,11-epoxidase, and resulted in a change in the kinetics from sigmoid to MichaelisMenten type. On the other hand, expressed CYP3A7-mediated CBZ 10,11-epoxidation was activated by sulfate conjugate steroids, such as pregnenolone 3-sulfate, 17␣-hydroxypregnenolone 3-sulfate, and dehydroepiandrosterone 3-sulfate (DHEA-S), whereas the unconjugated form corresponding to these three steroids did not activate the reaction. Especially, DHEA-S was found to be a potent activator of CBZ 10,11-epoxidation by expressed CYP3A7. The kinetic character of CBZ 10,11-epoxidation by CYP3A7 is Michaelis-Menten type regardless of the presence of DHEA-S. The presence of DHEA-S caused a decrease in K m and increase in V max for CYP3A7-mediated CBZ 10,11-epoxidation, whereas DHEA-S 16␣-hydroxylation was not affected by the coexistence of CBZ. In conclusion, CYP3A4 and CYP3A7-mediated CBZ 10,11-epoxidations are activated by different types of endogenous steroids. This is the first report regarding CYP3A7 cooperativity.

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“…9 CYP3A7 plays an important role in the metabolism of endogenous substrates, such as testosterone and dehydroepiandrosterone, as well as potentially toxic compounds such as retinoic acid. 10,11 The role of CYP3A7 in the metabolism and clearance of these and many exogenous substrates to which the fetus is exposed, as well as large inter-individual differences in fetal CYP3A7 expression level 12 have led to the suggestion that differences in CYP3A7 expression and/or activity could contribute to inter-individual differences in embryonic toxicity and teratogenicity. 13 Since CYP3A43 is expressed at very low levels in several tissues, including liver, prostate, and testis, 14 it is not believed to play a substantial role in drug metabolism and has not been investigated as extensively as other members of the subfamily.…”

Section: Introductionmentioning

confidence: 99%

Sequence diversity and haplotype structure at the human CYP3A cluster

et al. 2005

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The four members of the human CYP3A subfamily play important roles in the clearance of xenobiotics, hormones, and environmental compounds. Many SNPs at the CYP3A locus have been characterized, with several showing large allele frequency differences across populations. In addition to the effects of CYP3A SNPs on drug metabolism, recent studies have highlighted the potential for CYP3A variation in susceptibility to several common phenotypes, including hypertension and cancer. We previously showed that the CYP3A4 and CYP3A5 genes have a strong haplotype structure at varying frequencies across ethnic groups. Here, we extend our re-sequencing survey to the remaining CYP3A genes in the same cluster, CYP3A7 and CYP3A43. Our study identified a large number of SNPs in coding and conserved noncoding sequences, several of which are common. The combined data set allows us to investigate patterns of sequence variation and linkage disequilibrium at the entire CYP3A locus for use in future association studies.

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Differential catalytic properties in metabolism of endogenous and exogenous substrates among CYP3A enzymes expressed in COS-7 cells

Cited by 66 publications

References 33 publications

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

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

CYP3A4 and CYP3A7-Mediated Carbamazepine 10,11-Epoxidation Are Activated by Differential Endogenous Steroids

Sequence diversity and haplotype structure at the human CYP3A cluster

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