Impact of the OATP1B1 c.521T>C single nucleotide polymorphism on the pharmacokinetics of exemestane in healthy post-menopausal female volunteers.

WHAT IS KNOWN AND OBJECTIVE: OATP1B1 mediates the transport of a diverse range of amphiphilic organic compounds that include bile acids, steroid conjugates and hormones. This retrospective pharmacogenetic study was conducted to assess the impact of the OATP1B1 c.521T>C single nucleotide polymorphism (SNP) on the pharmacokinetics of the steroidal aromatase inhibitor drug exemestane in healthy volunteers. METHODS: Exemestane (25 mg) was administered orally to 14 healthy post-menopausal women. All of the 14 subjects were sampled for pharmacokinetic (PK) analyses and retrospectively genotyped for OATP1B1 c.521T>C (rs 4149056). RESULTS AND DISCUSSION: Of the 14 subjects enrolled in the study, five were carriers of the minor C allele (OATP1B1 c.521TC+CC) and the remaining nine were carriers of the OATP1B1 c.521TT genotype. PK was assessed over 8 hours post-dosing. Our results showed statistically significant differences (P=.04) in the plasma exemestane AUC0-8 between the OATP1B1 genotype groups. Our data also showed statistically significant differences (P=.04) in the plasma AUC0-8 of 17-hydroexemestane (the major biologically active metabolite) between the OATP1B1 genotype groups. WHAT IS NEW AND CONCLUSION: Our data suggest that the OAPTP1B1 c.521T>C SNP may influence exemestane pharmacokinetics in humans.

Plasma letrozole concentrations in postmenopausal women with breast cancer are associated with CYP2A6 genetic variants, body mass index, and age.

The associations between plasma letrozole concentrations and CYP2A6 and CYP3A5 genetic variants were tested in the Exemestane and Letrozole Pharmacogenomics (ELPH) trial. ELPH is a multicenter, open-label prospective clinical trial in women randomly assigned (n≈250 in each arm) to receive 2 years of treatment with either oral letrozole (2.5 mg/day) or oral exemestane (25 mg/day). CYP2A6 and CYP3A showed effects on letrozole metabolism in vitro. DNA samples were genotyped for variants in the CYP2A6 and CYP3A5 genes. Plasma letrozole concentrations showed high interpatient variability (>10-fold) and were associated significantly with CYP2A6 genotypes (P<0.0001), body mass index (BMI) (P<0.0001), and age (P=0.0035). However, CYP3A5 genotypes showed no association with plasma letrozole concentrations. These data suggest that CYP2A6 is the principal clearance mechanism for letrozole in vivo. CYP2A6 metabolic status, along with BMI and age, may serve as a biomarker of the efficacy of letrozole treatment or a predictor of adverse effects.

[Sociocultural aspects of albinism in Sub-Saharan Africa: mutilations and ritual murders committed in east Africa (Burundi and Tanzania)]. / Aspects socioculturels des albinos en Afrique Noire: des mutilations et crimes rituels perpétrés en Afrique de l'est (Burundi et Tanzanie).

This report presents an overview of the many sociocultural prejudices confronting albinos and their parents in Sub-Saharan Africa at each stage of life (infancy, adolescence, and adulthood). The birth of an albino child to two black parents has always been an enigma for African peoples. French-speaking and English-speaking populations in Central, East and South African countries have invented numerous myths to account for this event. Albinos are believed to possess good and evil magical powers. On the white magic side, some organs are believed to confer luck, health, and prosperity. For this reason albinos in Tanzania and Burundi are still in 2008 prey to ritual murders and mutilations to obtain various body parts such as arms, legs, and genitals for preparation of amulets. This barbaric and iniquitous practice has been severely condemned by authorities in both countries as well as by the European Parliament. To end these atrocities disseminating accurate medical information explaining the genetic basis of albinism will be necessary to eliminate ignorance and superstition.

[Seroanthropological studies of albino and melanoderm Bamiléké populations (Cameroon). ABO and Rhesus erythrocyte groups, hemoglobin S and taste sensitivity to phenylthiocarbamide]. / Etudes séroanthropologiques des populations albinos et mélanodermes bamilékés (Cameroun). Groupes érythrocytaires ABO et Rhésus, hémoglobine S et sensibilité gustative à la phénylthiocarbamide.

Human oculocutaneous albinism is a recessive autosomic hereditary disease with a prevalence of 1/8,500 in bamileke tribe (Cameroon). ABO and Rhesus red blood cell group repartition, presence of hemoglobin S, taste sensitivity for phenylthiocarbamid in a group of 100 albino bamileke subjects were compared with these of 100 black bamileke subjects. There is no significant difference for these genetic markers mentionned above between albino and black bamileke subjects.

Induced hepatotoxicity in female rats by aflatoxin B1 and ethynylestradiol interaction.

Female Sprague-Dawley rats were treated with a single ip dose of aflatoxin B1 (AFB1) (3 or 6 mg/kg). Twenty-four hours later and weekly until killed, some of the rats treated with AFB1 were given ethynylestradiol (EE) by gavage at the dose of 13 mg/kg. One, three, six, and nine months following the beginning of the experiment, animals were killed. Light microscopy of liver and histochemical determinations of gamma-glutamyltransferase (GGT) as well as the measurement of hepatic drug-metabolizing enzyme activities were investigated. The results show that AFB1 induced only very weak changes in the levels of different constituents studied. Thus, the mycotoxin did not affect GGT activity and increased epoxide hydrolase activity by a maximum of 42%. In contrast, EE significantly and progressively decreased (20 to 50%) the activity of UDP-glucuronosyltransferase (UDPGT) as well as the concentration of cytochrome P-450 and microsomal proteins. However, the estrogen increased the activity of epoxide hydrolase up to 150% as well as the activity of the hepatic (400%) and plasma (175%) GGT. The results also indicate that AFB1 amplified the EE-induced increase in liver weight and enhanced the depressive effects of the estrogen on microsomal proteins, cytochrome P-450, and UDPGT. Foci of cellular alteration which consisted of clear, acidophilic and basophilic cell lesions were seen in the livers of treated rats examined by light microscopy. These lesions were more prominent in the livers of animals given combinations of AFB1 and EE; they were accompanied by a strong intensity of GGT staining in the periportal area and a marked increase of the enzyme activity in the plasma (324%). From the sixth month, the livers of some animals treated with the combinations of AFB1 and EE showed hyperplastic nodules. This study indicates that the interaction between chronic administration of EE and a single ip injection of AFB1 induces hepatic lesions considered as possible forerunners of liver cell carcinomas. It also shows that GGT is a potential marker of preneoplastic lesions and may be used, therefore, in epidemiologic surveys in humans exposed to liver carcinogens such as the aflatoxins.

Effect of aflatoxin B1 on hepatic drug-metabolizing enzymes in female rats. Interaction with a contraceptive agent.

1. The effect of a contraceptive on aflatoxin B1 toxicity has been studied in female rats treated for 15 consecutive days with repeated doses of aflatoxin (0.40 mg/kg/day), norethindrone (0.60 mg/kg/day) and ethynylestradiol (0.012 mg/kg/day). 2. Increases occurred in hepatic microsomal cytochrome P-450 content (31%), and in the activities of epoxide hydrase (77%), UDP-glucuronyltransferase (67%) and gamma-glutamyltransferase (78%). 3. Aflatoxin alone caused a 22% increase in GSH S-epoxide transferase activity, whereas the contraceptive given alone or combined with aflatoxin increased the hepatic reduced glutathione. 4. The effect of aflatoxin plus contraceptive was not additive. 5. The effects caused by aflatoxin and the contraceptive were similar, and the contraceptive (depending on its progestogen/estrogen ratio), may modify aflatoxin toxicity by increasing the drug-metabolizing enzyme activities and the concentration of hepatic glutathione.

[Serum carotenoids and vitamin A in melanodermic and albino subjects in Cameroon]. / Caroténoïdes et vitamine A sériques au Cameroun chez des sujets mélanodermes et albinos.

Vitamin A nutritional status as assessed by carotenoid and vitamin A assays in sera collected in various parts of Cameroon prooved to be of good value. Palm oil rich diets lead to high seric carotenoid concentrations and tissular accumulation which is particularly visible on the palms and soles of melanodermic and albinos subjects.