Large interindividual variability in the <i>in vitro</i> formation of tamoxifen metabolites related to the development of genotoxicity

Coller, Janet K.; Krebsfaenger, Niels; Klein, Kathrin; Wolbold, Renzo; Nüssler, Andreas K.; Neuhaus, P.; Zanger, Ulrich M.; Eichelbaum, Michel; Mürdter, Thomas E.

doi:10.1046/j.1365-2125.2003.01970.x

Cited by 23 publications

(17 citation statements)

References 13 publications

(24 reference statements)

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“…Several lines of evidence obtained from a variety of experimental approaches clearly show a prominent role of CYP3A in TAM secondary metabolism: we have shown for the first time that the metabolism of N-desmethyl-TAM to ␣-hydroxy N-desmethyl-TAM and of 4-hydroxy-TAM to endoxifen is predominantly catalyzed by CYP3A, and we have confirmed CYP3A as the principal catalyst of N-desmethyl-TAM metabolism to N-didesmethyl-TAM and of 4-hydroxy-TAM metabolism to 3,4-dihydroxy-TAM, consistent with other reports (Dehal and Kupfer, 1999;Coller et al, 2004). These findings may have important implications.…”

Section: Tam Biotransformation To Its Primary Metabolitessupporting

confidence: 80%

“…␣-Hydroxy-TAM and its sulfated metabolites have been implicated in TAM-induced toxicity in vitro and animal studies (White, 2003). The present data and previous reports (White, 2003;Coller et al, 2004) suggest that CYP3A4 and CYP3A5 are important catalysts of TAM ␣-hydroxylation, raising the possibility that high CYP3A activity in patients may enhance TAM-induced toxicity. We have also provided the first evidence that 4Ј-and 3-hydroxy-TAM are formed in HLMs and that CYP2B6 (and probably CYP2C19) and CYP3A5, respectively, might be the principal catalysts of these reactions.…”

Section: Tam Biotransformation To Its Primary Metabolitessupporting

confidence: 57%

“…There is evidence that the primary metabolites of TAM are further oxidized by the human P450 system to a variety of important metabolites (Lonning et al, 1992;Dehal and Kupfer, 1999;Stearns et al, 2003;White, 2003;Coller et al, 2004). The potential significance of TAM secondary metabolism was suggested by recent studies that identified endoxifen as a potent antiestrogen metabolite of TAM (Stearns et al, 2003;Johnson et al, 2004;Lim et al, 2004).…”

mentioning

confidence: 97%

“…For example, the activity of CYP2D6 in the HLMs listed in Table 1 was 135 and 24.5 pmol/min/mg protein in HG23 and HG112, respectively (and undetectable in HG06), whereas that of CYP3A in HG112, HG23, and HG06 was 17,205, 3320, and 3000 pmol/min/mg protein, respectively. We specifically focused on CYP3A and CYP2D6 because there is evidence that CYP3A and CYP2D6, respectively, are important catalysts of TAM N-demethylation (Jacolot et al, 1991;Coller et al, 2004) and 4-hydroxylation (Crewe et al, 1997;Dehal and Kupfer, 1997). The relationship between the activity of individual P450s in these HLMs and CL int (Table 1) was tested using linear regression analysis to obtain preliminary information on the P450s catalyzing the low-and high-affinity component.…”

Section: Hlms Tam To N-desmethyl-tammentioning

confidence: 99%

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Comprehensive Evaluation of Tamoxifen Sequential Biotransformation by the Human Cytochrome P450 System in Vitro: Prominent Roles for CYP3A and CYP2D6

Desta

Ward

Soukhova

et al. 2004

J Pharmacol Exp Ther

576

484

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We performed comprehensive kinetic, inhibition, and correlation analyses in human liver microsomes and experiments in expressed human cytochromes P450 (P450s) to identify primary and secondary metabolic routes of tamoxifen (TAM) and the P450s catalyzing these reactions at therapeutically relevant concentrations. N-Desmethyl-TAM formation catalyzed by CYP3A4/5 was quantitatively the major primary metabolite of TAM; 4-hydroxy-TAM formation catalyzed by CYP2D6 (and other P450s) represents a minor route. Other minor primary metabolites include ␣ -, 3-, and 4Ј-hydroxyTAM and one unidentified metabolite (M-I) and were primarily catalyzed by CYP3A4, CYP3A5, CYP2B6/2C19, and CYP3A4, respectively. TAM secondary metabolism was examined using N-desmethyland 4-hydroxy-TAM as intermediate substrates. N-Desmethyl-TAM was predominantly biotransformed to ␣-hydroxy N-desmethyl-, N-didesmethyl-, and 4-hydroxy N-desmethyl-TAM (endoxifen), whereas 4-hydroxy-TAM was converted to 3,4-dihydroxyTAM and endoxifen. Except for the biotransformation of N-desmethyl-TAM to endoxifen, which was exclusively catalyzed by CYP2D6, all other routes of N-desmethyl-and 4-hydroxy-TAM biotransformation were catalyzed predominantly by the CYP3A subfamily. TAM and its primary metabolites undergo extensive oxidation, principally by CYP3A and CYP2D6 to metabolites that exhibit a range of pharmacological effects. Variable activity of these P450s, brought about by genetic polymorphisms and drug interactions, may alter the balance of TAM effects in vivo.

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Section: Tam Biotransformation To Its Primary Metabolitessupporting

confidence: 80%

Section: Tam Biotransformation To Its Primary Metabolitessupporting

confidence: 57%

mentioning

confidence: 97%

Section: Hlms Tam To N-desmethyl-tammentioning

confidence: 99%

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Comprehensive Evaluation of Tamoxifen Sequential Biotransformation by the Human Cytochrome P450 System in Vitro: Prominent Roles for CYP3A and CYP2D6

Desta

Ward

Soukhova

et al. 2004

J Pharmacol Exp Ther

576

484

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“…4-hydroxylation is mainly catalyzed by CYP2D6 whereas formation of the N-oxide metabolite is catalyzed by flavin-containing monooxygenases. CYP2C19, CYP2C9, CYP1A2 and CYP2B6 complement N-desmethylation and 4-hydroxylation [2][3][4][5][6][7][8]. The amount of tamoxifen metabolites formed is highly variable between individual patients.…”

Section: Introductionmentioning

confidence: 99%

TGFβ2 and TβRII are valid molecular biomarkers for the antiproliferative effects of tamoxifen and tamoxifen metabolites in breast cancer cells

Buck

Coller

Mürdter

et al. 2007

Breast Cancer Res Treat

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Response to treatment with the antiestrogen tamoxifen is variable and at least partially due to its highly complex metabolism. Tamoxifen is transformed by polymorphic and inducible cytochrome P450 enzymes to a large number of metabolites with varying biological activities. The estrogen receptor dependent growth inhibitory effect of antiestrogens is mediated by activation of antiproliferative Transforming Growth Factor beta (TGFbeta) signal transduction pathways. The aim of the present study was to establish if TGFbeta2 or TGFbeta receptor II (TbetaRII), could be used as markers to assess the pharmacological potency of tamoxifen and its metabolites. Consequently, we analyzed the growth inhibitory effect of tamoxifen and its major metabolites and explored whether it correlated with their capacity to induce TGFbeta2 and TbetaRII expression. Human breast cancer cells (MCF-7 and T47D) were treated with tamoxifen and tamoxifen metabolites and mRNA expression of TGFbeta2 and TbetaRII was analyzed by quantitative RT-PCR. Only two metabolites 4-hydroxytamoxifen and N-desmethyl-4-hydroxytamoxifen had significant antiproliferative activity and were able to induce TGFbeta2 and TbetaRII. Plasma concentrations of these metabolites are usually very low in patients. However, even minor growth inhibitory effects at concentrations which are below the limit of quantification in plasma samples resulted in clearly discernible effects on expression of TGFbeta2 and TbetaRII. Taken together, our data demonstrate that TGFbeta2 and TbetaRII are very specific and sensitive biomarkers for the antiestrogenic activity of tamoxifen metabolites in breast cancer.

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Interactions of tamoxifen, N‐desmethyltamoxifen and 4‐hydroxytamoxifen with P‐glycoprotein and CYP3A

Bekaii‐Saab

Perloff

Weemhoff

et al. 2004

Biopharm & Drug Disp

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The effects of tamoxifen, N-desmethyltamoxifen and 4-hydroxytamoxifen on transport attributable to P-glycoprotein were studied using Caco-2 cell monolayers in a transwell system, with rhodamine-123 as an index substrate for inhibition studies. The three compounds did not demonstrate differential flux between basal-apical and apical-basal directions in Caco-2 monolayers. The mean IC50 values for inhibition of rhodamine-123 transport were: 29 microM for tamoxifen; 26 microM for N-desmethyltamoxifen; and 7.4 microM for 4-hydroxytamoxifen. The three compounds were also evaluated as potential inhibitors of human CYP3A based on an in vitro model using triazolam hydroxylation by human liver microsomes as an index reaction. Mean (+/-SE) IC50 values versus formation of alpha-hydroxy-triazolam and 4-hydroxy-triazolam in human liver microsomes were, respectively: 23.5 (+/-3.9) and 18.4 (+/-5.3) microM for tamoxifen; 10.2 (+/-1.7) and 9.2 (+/-1.5) microM for N-desmethyltamoxifen; and 2.6 (+/-0.5) and 2.7 (+/-0.3) microM for 4-hydroxytamoxifen. Thus, tamoxifen, N-desmethyltamoxifen and 4-hydroxytamoxifen, do not appear to be substrates for transport by P-glycoprotein. However, tamoxifen has the potential to inhibit transport mediated by P-glycoprotein as well as CYP3A-mediated metabolism. Inhibitory effects of the principal metabolites, N-desmethyltamoxifen and 4-hydroxytamoxifen, may exceed those of the parent drug. Tamoxifen, and possibly its metabolites, may have the potential to cause drug interactions by inhibiting both drug transport and metabolism. This possibility requires further evaluation in clinical studies.

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Large interindividual variability in the in vitro formation of tamoxifen metabolites related to the development of genotoxicity

Cited by 23 publications

References 13 publications

Comprehensive Evaluation of Tamoxifen Sequential Biotransformation by the Human Cytochrome P450 System in Vitro: Prominent Roles for CYP3A and CYP2D6

Comprehensive Evaluation of Tamoxifen Sequential Biotransformation by the Human Cytochrome P450 System in Vitro: Prominent Roles for CYP3A and CYP2D6

TGFβ2 and TβRII are valid molecular biomarkers for the antiproliferative effects of tamoxifen and tamoxifen metabolites in breast cancer cells

Interactions of tamoxifen, N‐desmethyltamoxifen and 4‐hydroxytamoxifen with P‐glycoprotein and CYP3A

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