Metabolism of tamoxifen by isolated rat hepatocytes

McCague, Raymond; Parr, Iris B.; Leclercq, Guy; Leung, On-Tai; Jarman, Michael

doi:10.1016/0006-2952(90)90427-m

Cited by 26 publications

(5 citation statements)

References 25 publications

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“…There are additional examples of investigational anticancer agents that are also glucuronidated. Drugs such as topotecan, doxorubicin and 4-hydroxytamoxifen are known to be glucuronidated; however, the specific UGT isozymes involved in these reactions are as yet unknown (McCague et al, 1990;Platzer et al, 1998;Rosing et al, 1998;Andersen et al, 1999). Estrogens, progestins and androgens are also glucuronidated, and may be an important means of circulation of the inactive form of the hormone in the body, although sulfation appears to be a predominant depot mechanism for estrogens.…”

Section: The Ugt Superfamilymentioning

confidence: 99%

Uridine diphosphoglucuronosyltransferase pharmacogenetics and cancer

2006

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The uridine diphosphoglucuronosyltransferases (UGTs) belong to a superfamily of enzymes that catalyse the glucuronidation of numerous endobiotics and xenobiotics. Several human hepatic and extrahepatic UGT isozymes have been characterized with respect to their substrate specificity, tissue expression and gene structure. Genetic polymorphisms have been identified for almost all the UGT family members. A wide variety of anticancer drugs, dietary chemopreventives and carcinogens are known to be conjugated by members of both UGT1A and UGT2B subfamilies. This review examines in detail each UGT isozyme known to be associated with cancer and carcinogenesis. The cancer-related substrates for several UGTs are summarized, and the functionally relevant genetic polymorphisms of UGTs are reviewed. A number of genotype-phenotype association studies have been carried out to characterize the role of UGT pharmacogenetics in several types of cancer, and these examples are discussed here. In summary, this review focuses on the role of the human UGT genetic polymorphisms in carcinogenesis, chemoprevention and cancer risk.

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Section: The Ugt Superfamilymentioning

confidence: 99%

Uridine diphosphoglucuronosyltransferase pharmacogenetics and cancer

2006

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“…Actually, the anti-estrogenic and antiproliferative activities of OHTAM in vitro are much stronger as compared with TAM (Borgna and Rochefort, 1981;Etienne et al, 1989), but the pharmacological relevance of OHTAM has been questioned (McCague et al, 1990) due to its low serum concentrations (Lien et al, 1987;MacCallum et al, 1996). However, the strong affinity of OHTAM for biomembrane proteins (Custo´dio et al, 1991) and its higher partitioning in the lipid bilayer as compared with TAM (Custo´-dio et al, 1991), perturbing the membrane lipid-protein interface (Custo´dio et al, 1993b) suggest that OHTAM may accumulate in tissues, reaching there the required effective concentrations for its cytotoxic effects, as described by Lien et al (1991).…”

Section: Introductionmentioning

confidence: 99%

Hydroxytamoxifen interaction with human erythrocyte membrane and induction of permeabilization and subsequent hemolysis

Silva

Madeira

Almeida

et al. 2001

Toxicology in Vitro

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4-Hydroxytamoxifen (OHTAM) is the most active metabolite of the widely prescribed anticancer drug tamoxifen (TAM) used in breast cancer therapy. This work describes the effects of OHTAM on isolated human erythrocytes, using standardized test conditions, to check for a putative contribution to the TAM-induced hemolysis and to study basic mechanisms involved in the interaction of OHTAM with cell membranes. Incubation of isolated human erythrocytes with relatively high concentrations of OHTAM results in a concentration-dependent hemolysis, its hemolytic effect being about one-third of that induced by TAM. OHTAMinduced hemolysis is prevented by either a-tocopherol (a-T) or a-tocopherol acetate (a-TAc) and it occurs in the absence of oxygen consumption and hemoglobin oxidation, ruling out the oxidative damage of erythrocytes. However, OHTAM remarkably increases the osmotic fragility of erythrocytes, increasing the susceptibility of erythrocytes to hypotonic lysis. Additionally, the hemoglobin release induced by OHTAM is preceded by a rapid efflux of intracellular K + . Therefore, our data suggest that OHTAM-induced hemolysis does not contribute to TAM-induced hemolytic anemia and it is a much weaker toxic drug as compared with TAM. Moreover, at variance with the membrane disrupting effects of TAM, OHTAM promotes perturbation of the membrane's backbone region due to its strong binding to proteins with consequent formation of membrane paths of permeability to small solutes and retention of large solutes like hemoglobin, followed by osmotic swelling and cell lysis. The prevention of OHTAM-induced hemolysis by a-T and a-TAc is probably committed to the permeability sealing resulting from structural stabilization of membrane. #

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“…This separationdesalting process was repeated until we obtained the quantities required for our metabolic studies. (13). To a solution of regioisomers 10 and 11 (310 mg, 0.35 mmol) in THF (5 ml) was added HF Á Pyr (0.6 ml).…”

Section: Resultsmentioning

confidence: 99%

“…13 We suspected that the low solubility of acolbifene in the solvents used for these reactions was responsible for this problem. A solution to this issue has been the conversion of acolbifene into the more soluble monoTBDMS ethers.…”

Section: Introductionmentioning

confidence: 98%

Synthesis and deuterium labelling of the pure selective estrogen receptor modulator (SERM) acolbifene glucuronides

Sancéau

Larouche

Caron

et al. 2007

Labelled Comp Radiopharmac

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Acolbifene (EM-652 Á HCl, SCH 57068 Á HCl), a highly potent and orally active selective estrogen receptor modulator (SERM), is at late stage clinical development for the treatment of estrogen-sensitive breast cancer. Acolbifene-7-glucuronide 1 (major) and acolbifene-4 0 -glucuronide 2 (minor) were identified as metabolites of acolbifene in the human. The two monoglucuronides and a diglucuronide 3 as well as the corresponding 2 H-labelled derivatives 4-6 were synthesised for use as preclinical and clinical standards for LC-MS/MS analysis. All glucuronides were prepared by the Schmidt glycosylation of monoprotected acolbifene with a glucuronyl imidate at À108C to prevent epimerisation at the C-2 position. The two monoglucuronides 1 and 2 of acolbifene were separated by semi-preparative HPLC. Incorporation of three deuteriums was achieved by alkylation of chromanone 15 with C 2 H 3 MgI followed by dehydration with C

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Metabolism of tamoxifen by isolated rat hepatocytes

Cited by 26 publications

References 25 publications

Uridine diphosphoglucuronosyltransferase pharmacogenetics and cancer

Uridine diphosphoglucuronosyltransferase pharmacogenetics and cancer

Hydroxytamoxifen interaction with human erythrocyte membrane and induction of permeabilization and subsequent hemolysis

Synthesis and deuterium labelling of the pure selective estrogen receptor modulator (SERM) acolbifene glucuronides

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