Sulfation of afimoxifene, endoxifen, raloxifene, and fulvestrant by the human cytosolic sulfotransferases (SULTs): A systematic analysis

Hui, Ying; Luo, Lijun; Zhang, Lingtian; Kurogi, Katsuhisa; Zhou, Chun; Sakakibara, Yoichi; Suiko, Masahito; Liu, Ming‐Cheh

doi:10.1016/j.jphs.2015.06.004

Cited by 19 publications

(11 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, no pharmacokinetic data are available and no further progress on pre-clinical studies have been reported since 2010. Indeed, these attempts focused on modifications made primarily to the long alkyl chain to increase polarity and solubility but failed to address the main problem that is responsible for the poor bioavailability of fulvestrant, that is, fulvestrant undergoes rapid and extensive O-glucuronidation [ 21 – 22 ] and O-sulfation [ 23 – 24 ] to form polar metabolites that are inactivated and undergo rapid systemic clearance.…”

Section: Introductionmentioning

confidence: 99%

Metabolism, pharmacokinetics, and bioavailability of ZB716, a Steroidal Selective Estrogen Receptor Downregulator (SERD)

et al. 2017

View full text Add to dashboard Cite

ZB716 is a selective estrogen receptor downregulator (SERD) with excellent oral bioavailability and superior efficacy. In this study, we investigate the in vitro and in vivo metabolism and the pharmacokinetics of ZB716 by incubation with liver microsomes, liver cytosol, and by orally dosing rodents. Metabolic products were identified and quantified by a combination of liquid chromatography and tandem +mass spectrometry. The metabolic profile of ZB716 showed fulvestrant and ZB716-sulfone as the two major oxidative metabolites. ZB716 also underwent some degree of sulfation and glucuronidation in vitro. The major oxidative metabolites of ZB716 were found in rat plasma, feces, and urine samples. No sulfation and glucuronidation metabolites from ZB716 were found in plasma. Limited amounts of sulfate conjugates and glucuronides of ZB716 were detected in feces. The glucuronidation on 3-OH position of fulvestrant was the main metabolite found in urine, suggesting that this specific site of phase 2 metabolism is blocked in ZB716 and formation of glucuronide 3-fulvestrant must be preceded by metabolic transformation of ZB716 to fulvestrant. The pharmacokinetic study of ZB716 showed a half-life (t1/2) at 17.03 hour, the area under curve value (AUC) of 1451.82 ng/ml*h, and the maximum plasma concentration (Cmax) at 158.12 ng/mL reached at 2 h after a single dose of 10 mg/kg by oral gavage. Overall this study elucidated important metabolic characteristics of ZB716, an oral SERD that has demonstrated superior bioavailability and efficacy in preclinical studies conducted so far.

show abstract

Section: Introductionmentioning

confidence: 99%

Metabolism, pharmacokinetics, and bioavailability of ZB716, a Steroidal Selective Estrogen Receptor Downregulator (SERD)

et al. 2017

View full text Add to dashboard Cite

show abstract

“…SULT1A1 is generally recognized as the major xenobiotic-metabolizing SULT isoform that is responsible for the metabolism of reactive compounds (e.g., benzylic alcohols and aromatic hydroxylamines), which are associated with carcinogenesis 9 . Sulfate conjugation by other SULT enzymes (SULT1A3, SULT1E1 and SULT1B1) may result in the activation or inactivation of anti-cancer drugs (e.g., raloxifene, sesamol, fulvestrant, and resveratrol), thereby affecting their anti-tumor effects 10–13 . In addition, Huang LR et al .…”

Section: Introductionmentioning

confidence: 99%

LC-MS/MS quantification of sulfotransferases is better than conventional immunogenic methods in determining human liver SULT activities: implication in precision medicine

Xie

Yan

Jiamei

et al. 2017

Sci Rep

View full text Add to dashboard Cite

This study aims to determine whether enzyme activities are correlated with protein amounts and mRNA expression levels of five major human sulfotransferase (SULT) enzymes in 10 matched pericarcinomatous and hepatocellular carcinoma liver samples. The MRM UHPLC-MS/MS method, Western blot and RT-PCR were used along with SULT activity measurement using probe substrates. The LC-MS/MS method was specific for all five tested SULTs, whereas Western blot was specific for only two isoforms. The activities of SULT1A1, SULT1B1, SULT1E1 and SULT2A1 in 9 of 10 samples showed a significant decrease in tumor tissues relative to matched pericarcinomatous tissues, whereas the activities of SULT1A3 in 7 of 10 samples increased. The turnover numbers of SULTs did not change, except for SULT1A1. A generally high degree of correlations was observed between SULT activities and protein amounts (r2 ≥ 0.59 except one), whereas a low degree of correlations was observed between SULT activities and mRNA expression levels (r2 ≤ 0.48 except one). HCC reduced the SULT activities via impaired protein amounts. LC-MS/MS quantification of SULTs is highly reliable measurement of SULT activities, and may be adopted for implementing precision medicine with respect to drugs mainly metabolized by SULTs in healthy and HCC patients.

show abstract

“…SULT1E1 and SULT2A1 mRNA levels were below the detection limit in both cell lines [20]. As SULT1C4 mRNA only has been found at high levels in human fetal lung, liver, small intestine, and kidney, and at low levels in adult kidney, ovary, and spinal cord but not in breast tissue [24], we hypothesized that SULT1A1 may mainly contribute to curcumin sulfation in ZR-75-1 and MDA-MB-231 cells leading to decreased anticancer activity. Our hypothesis is further supported by data of Irison and coworkers who indeed showed that curcumin sulfate has less biological activities compared to curcumin [11].…”

Section: Discussionmentioning

confidence: 98%

Metabolism of Curcumin in Human Breast Cancer Cells: Impact of Sulfation on Cytotoxicity

et al. 2017

View full text Add to dashboard Cite

Curcumin is a natural polyphenol with promising anticancer properties that undergoes pronounced metabolism in humans. In order to determine whether metabolism of curcumin also occurs in tumor cells and whether biotransformation has any impact on cytotoxicity, metabolism experiments were conducted with hormone-dependent ZR-75-1 and hormone-independent MDA-MB-231 human breast cancer cells. By using HPLC-ESI-Qq-TOF-MS, it was possible to identify one main metabolite, namely curcumin sulfate, in both cell lines. Its concentration in the cytoplasm and culture medium was 1.6- to 1.7-fold higher in ZR-75-1 cells than in MDA-MB-231 cells, concomitant with a 2-fold higher IC value in the ZR-75-1 cell line (14 µM compared to 7.3 µM). The net result of sulfation seems to lower the intracellular concentration of curcumin, thereby decreasing its growth inhibitory activity. Interestingly, for the first time, we also found the formation of a curcumin dimer in the cytoplasm but not in the cellular medium of both cell lines. Compared to curcumin sulfate, however, its maximal intracellular concentrations were up to 4-fold lower, indicating only a minor contribution to the overall curcumin clearance. In conclusion, our data elucidated the metabolism of curcumin in breast cancer cells, which must be considered in humans following oral uptake of dietary curcumin as a chemopreventive agent.

show abstract

Sulfation of afimoxifene, endoxifen, raloxifene, and fulvestrant by the human cytosolic sulfotransferases (SULTs): A systematic analysis

Cited by 19 publications

References 30 publications

Metabolism, pharmacokinetics, and bioavailability of ZB716, a Steroidal Selective Estrogen Receptor Downregulator (SERD)

Metabolism, pharmacokinetics, and bioavailability of ZB716, a Steroidal Selective Estrogen Receptor Downregulator (SERD)

LC-MS/MS quantification of sulfotransferases is better than conventional immunogenic methods in determining human liver SULT activities: implication in precision medicine

Metabolism of Curcumin in Human Breast Cancer Cells: Impact of Sulfation on Cytotoxicity

Contact Info

Product

Resources

About