Tamoxifen metabolism predicts drug concentrations and outcome in premenopausal patients with early breast cancer.

Tamoxifen is the standard-of-care treatment for estrogen receptor-positive premenopausal breast cancer. We examined tamoxifen metabolism via blood metabolite concentrations and germline variations of CYP3A5, CYP2C9, CYP2C19 and CYP2D6 in 587 premenopausal patients (Asians, Middle Eastern Arabs, Caucasian-UK; median age 39 years) and clinical outcome in 306 patients. N-desmethyltamoxifen (DM-Tam)/(Z)-endoxifen and CYP2D6 phenotype significantly correlated across ethnicities (R(2): 53%, P<10(-77)). CYP2C19 and CYP2C9 correlated with norendoxifen and (Z)-4-hydroxytamoxifen concentrations, respectively (P<0.001). DM-Tam was influenced by body mass index (P<0.001). Improved distant relapse-free survival (DRFS) was associated with decreasing DM-Tam/(Z)-endoxifen (P=0.036) and increasing CYP2D6 activity score (hazard ratio (HR)=0.62; 95% confidence interval (CI), 0.43-0.91; P=0.013). Low (<14 nM) compared with high (>35 nM) endoxifen concentrations were associated with shorter DRFS (univariate P=0.03; multivariate HR=1.94; 95% CI, 1.04-4.14; P=0.064). Our data indicate that endoxifen formation in premenopausal women depends on CYP2D6 irrespective of ethnicity. Low endoxifen concentration/formation and decreased CYP2D6 activity predict shorter DRFS.

Novel mutation, L371V, causing multigenerational Gaucher disease in a Lebanese family.

We have identified six individuals over three generations within a Lebanese-Arab family affected with Gaucher disease. This family is unusual and informative because affected members are homozygous for a previously unidentified mutation, L371V. Clinical symptoms begin in early childhood and progress to moderately severe involvement by young adulthood. There is significant anemia, thrombocytopenia, and bony involvement, but no mental deterioration. The phenotype is more severe than the phenotype observed in the common mutation associated with type 1 Gaucher disease, N370S. It is unknown whether L371V is a private mutation limited to this family, or will prove to be a common mutation within the Lebanese population.

Prostacyclin-enhanced calcium sequestration by microsomes isolated from rat left ventricle.

The objective of these experiments was to investigate the direct effect of prostacyclin on calcium binding and uptake by microsomal vesicles isolated from rat left ventricle. The protein content of the preparation was found to be 2.73 +/- 0.18 mg microsomal protein/g of left ventricular wet weight. Steady-state calcium binding and uptake by microsomal vesicles was reached at 6 minutes in control animals and 20 sec in prostacyclin-treated experiments. Prostacyclin increased steady-state calcium binding and uptake from a control of 52.48 +/- 4.16 up to 109.31 +/- 3.06 nmol/mg protein (p less than 0.05) and from 238.07 +/- 12.37 up to 314.85 +/- 1.23 nmol/mg protein (p less than 0.05) respectively. Doubling the concentration of prostacyclin from initial dose of 1.2 x 10(-8) M did not alter calcium binding and uptake further.

Prostacyclin-inhibition of lysine accumulation by the rat left ventricle.

1. Left ventricular slices of male Sprague-Dawley rats were incubated with a fixed concentration of 0.5 microCi/ml 3H-lysine and several concentrations of unlabelled lysine ranging from 0.2 to 5.0 mM in control and prostacyclin-treated experiments. The time of incubation ranged from 0.5 to 90 min. 2. Left ventricular slices were cut to have an optimal thickness of 0.47 +/- 0.09 mm. 3. Lysine was taken up against a concentration gradient. Saturation was reached at 0.5 mM and steady state accumulation of lysine was attained within 60 min. 4. Prostacyclin in concentrations ranging from 1.2 x 10(-8) to 4.8 x 10(-8) M inhibited lysine transport in left ventricular slices significantly (P less than 0.01).

The biosynthesis of C 55 polyprenols by a cell-free preparation of Lactobacillus plantarum.

A cell-free supernatant of lysates of Lactobacillus plantarum catalyses the synthesis of lipids from [2-(14)C]mevalonate. Of the added mevalonate, 7.5% is incorporated into lipids, which were fractionated into five components. About 4% of the radioactivity in these lipids co-chromatographs with compounds shown by mass spectrometry, n.m.r. and i.r. spectroscopy to be C(55) polyprenols, and about 2% co-chromatographs with a hexamer. The rest of the radioactivity is in more complex fractions. Analysis by mass spectrometry, n.m.r. and i.r. spectroscopy shows that the major C(55) polyprenol is undecaprenol, accompanied by an isomer containing one reduced isoprene unit. A Kuhn-Roth degradation of [(14)C]polyprenols indicates that the supernatant catalyses synthesis of these compounds de novo.

Mevalonate metabolism in supernatant fractions of lysates of Lactobacillus plantarum.

The supernatant fractions of lysates of Lactobacillus plantarum metabolize mevalonate into lipids. Adenosine triphosphate and uridine, as well as related compounds, and reduced nicotinamide adenine dinucleotide phosphate or reduced nicotinamide adenine dinucleotide stimulate this process. To obtain very active supernatant fractions, the method of lysis is modified to include polyamines during lysozyme treatment of cells and subsequent shocking with citrate buffer.