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Clin Pharmacol Ther. 2002 Aug;72(2):192-9.
Effect of sex and menstrual cycle phase on cytochrome P450 2C19 activity with omeprazole used as a biomarker.

Kim MJ, Bertino JS Jr, Gaedigk A, Zhang Y, Sellers EM, Nafziger AN.

Clinical Pharmacology Research Center, Department of Medicine, Bassett Healthcare, One Atwell Road, Cooperstown, NY 13326-1394, USA.

BACKGROUND: Literature addressing the effect of sex on cytochrome P450 (CYP) 2C19 activity is conflicting. The exogenous female sex steroid hormones used in oral contraceptives are believed to significantly inhibit CYP2C19 activity. However, the effect of variations in endogenous sex steroid concentrations throughout the menstrual cycle has not been investigated. OBJECTIVE: The objective of this study was to determine the effects of sex and menstrual cycle phase on CYP2C19 activity by using omeprazole. METHODS: White subjects with body weights between 45 and 66 kg received a single oral dose of 30 mg omeprazole. Those with weights of 67 to 90 kg received a dose of 40 mg. Twelve female subjects were phenotyped during the midfollicular and midluteal phases of the menstrual cycle for 3 complete cycles. Twelve male subjects were phenotyped every 14 days for 12 weeks. The 2-hour postdose plasma concentration ratio of omeprazole to 5'-hydroxyomeprazole was used as a measure of CYP2C19 activity. All subjects were genotyped for CYP2C19*2 and *3 alleles. RESULTS: Twelve women and 8 men were extensive metabolizers (EMs) with a CYP2C19*1/*1 genotype, whereas 4 male subjects were heterozygous (CYP2C19*1/*2). Median metabolic ratios during the midfollicular and midluteal visits were 0.845 and 0.930, respectively (P =.7). Sex had no effect on CYP2C19 activity in CYP2C19*1/*1 EMs (0.875 for men versus 1.070 for women, P =.140). The median metabolic ratios of all individuals with 2C19*1/*1 and *1/*2 genotypes were 0.94 and 3.75, respectively. CONCLUSION: There is no sex difference in CYP2C19 activity in healthy white CYP2C19*1/*1 EMs with the omeprazole ratios. A gene-dose effect was observed. In addition, variations in endogenous sex steroid concentrations throughout the menstrual cycle did not influence CYP2C19 activity.

online pharmacy ref. source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12189366&dopt=Abstract

Diabetologia. 2002 Aug;45(8):1111-9. Epub 2002 Jul 04.
Defective amplification of the late phase insulin response to glucose by GIP in obese Type II diabetic patients.

Vilsboll T, Krarup T, Madsbad S, Holst JJ.

Department of Internal Medicine F, Gentofte Hospital, University of Copenhagen, Niels Andersens Vej 65, 2900 Hellerup, Denmark. tiventoftehosp.kbhamt.dk

AIMS/HYPOTHESIS: Glucagon-like-peptide-1 (GLP-1) is strongly insulinotropic in patients with Type II (non-insulin-dependent) diabetes mellitus, whereas glucose-dependent insulinotropic polypeptide (GIP) is less effective. Our investigation evaluated "early" (protocol 1) - and "late phase" (protocol 2) insulin and C-peptide responses to GLP-1 and GIP stimulation in patients with Type II diabetes. METHODS: Protocol 1: eight Type II diabetic patients and eight matched healthy subjects received i.v. bolus injections of GLP-1(2.5 nmol) or GIP(7.5 nmol) concomitant with an increase of plasma glucose to 15 mmol/l. Protocol 2: eight Type II diabetic patients underwent a hyperglycaemic clamp (15 mmol/l) with infusion (per kg body weight/min) of either: 1 pmol GLP-1 (7-36) amide (n=8), 4 pmol GIP (n=8), 16 pmol GIP (n=4) or no incretin hormone (n=5). For comparison, six matched healthy subjects were examined. RESULTS: Protocol 1: Type II diabetic patients were characterised by a decreased "early phase" response to both stimuli, but their relative response to GIP versus GLP-1 stimulation was exactly the same as in healthy subjects [insulin (C-peptide): patients 59+/-9% (74+/-6%) and healthy subjects 62+/-5% (71+/-9%)]. Protocol 2, "Early phase" (0-20 min) insulin response to glucose was delayed and reduced in the patients, but enhanced slightly and similarly by GIP and GLP-1. GLP-1 augmented the "late phase" (20-120 min) insulin secretion to levels similar to those observed in healthy subjects. In contrast, the "late phase" responses to both doses of GIP were not different from those obtained with glucose alone. Accordingly, glucose infusion rates required to maintain the hyperglycaemic clamp in the "late phase" period (20-120 min) were similar with glucose alone and glucose plus GIP, whereas a doubling of the infusion rate was required during GLP-1 stimulation. CONCLUSION/INTERPRETATION: Lack of GIP amplification of the late phase insulin response to glucose, which contrasts markedly to the normalising effect of GLP-1, could be a key defect in insulin secretion in Type II diabetic patients.

online pharmacy ref. source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12189441&dopt=Abstract

Diabetologia. 2002 Aug;45(8):1142-53. Epub 2002 Jun 28.
Expression profile of MODY3/HNF-1alpha protein in the developing mouse pancreas.

Nammo T, Yamagata K, Hamaoka R, Zhu Q, Akiyama TE, Gonzalez FJ, Miyagawa J, Matsuzawa Y.

Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University, Japan.

AIMS/HYPOTHESIS: One subtype of MODY (MODY3) results from the heterozygous mutation of a hepatocyte nuclear factor (HNF)-1alpha. The pattern of HNF-1alpha expression in the normal pancreas has not been determined. This study aimed to clarify the profile of HNF-1alpha protein expression in the developing mouse pancreas. METHODS: Double immunofluorescence staining was carried out for HNF-1alpha and pancreatic hormones or transcription factors (PDX-1, Pax6, Isl1, and Nkx2.2). The expression of these transcription factors was also studied in the beta cells of HNF-1 alpha mutant mice. RESULTS: HNF-1alpha was expressed by both endocrine and exocrine cells of the pancreas. Double immunofluorescence staining showed that HNF-1alpha was expressed in the nuclei of alpha cells, beta cells, delta cells, and pancreatic polypeptide (PP) cells. HNF-1alpha was first detected in most pancreatic epithelial cells on embryonic day 10.5 (E10.5), and hormone-positive endocrine cells and amylase-positive cells expressed HNF-1alpha on E15.5. Most of the Pax6-, Isl1-, or PDX-1-positive cells showed co-expression of HNF-1alpha. However, HNF-1alpha immunoreactivity was not observed in 36.0% of Nkx2.2-positive cells. Expression of Nkx2.2, Isl1 and Pax6 seemed to be normal in the beta cells of transgenic mice with dominant negative overexpression of HNF-1alpha. Expression of PDX-1 did not change in the beta cells of pre-diabetic HNF-1 alpha (-/-) mice, but expression was markedly decreased in the diabetic stage. CONCLUSION/INTERPRETATION: HNF-1alpha is expressed by both endocrine cells and exocrine cells of the pancreas from the foetal stage along with other transcription factors, so HNF-1alpha might play a role during development.

online pharmacy ref. source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12189445&dopt=Abstract

Clin Rheumatol. 2002 Aug;21(4):289-93.
ACTH, cortisol and prolactin in active rheumatoid arthritis.

Zoli A, Lizzio MM, Ferlisi EM, Massafra V, Mirone L, Barini A, Scuderi F, Bartolozzi F, Magaro M.

Istituto di Medicina Interna e Geriatria, Divisione di Reumatologia, Universita Cattolica del Sacro Cuore A Gemelli, Rome, Italy.

Prolactin (PRL) and glucocorticoids are hormones involved in the regulation of the immune system. Rheumatoid arthritis (RA) is an inflammatory condition that presents a diurnal rhythm of disease activity. ACTH, PRL, cortisol, IL-1 beta and TNF-alpha circadian rhythms have been studied in active RA (aRA) to evaluate a possible relationship between the neuroendocrine system and immunological activity in rheumatoid patients. ACTH, PRL, cortisol, PRL/cortisol ratio and IL-1 beta and TNF-alpha levels were determined in aRA patients and in control subjects at 6.00, 10.00, 14.00, 18.00, 22.00 and 02.00 h. In aRA patients we observed lower ACTH and cortisol levels at 22.00 h and 2.00 h, respectively and higher PRL and PRL/cortisol ratio at 2.00 h when compared to controls. IL-1 beta and TNF-alpha reached their highest serum levels in aRA patients at 2.00 and 6.00 h. This study provides evidence that in aRA there could be a temporary and probably causal relationship between diurnal disease activity, hormonal disequilibrium and cytokine secretion. An imbalance in favour of proinflammatory hormones (PRL and cytokines) as opposed to levels of anti-inflammatory hormones could be responsible for the diurnal rhythm of activity disease observed in aRA patients.

online pharmacy ref. source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12189455&dopt=Abstract

Hum Genet. 2002 Aug;111(2):219-24. Epub 2002 Jul 16.
Functional characterization of a natural variant of luteinizing hormone.

Liao WX, Goh HH, Roy AC.

Department of Obstetrics and Gynaecology, National University of Singapore, National University Hospital, Lower Kent Ridge Road, Singapore 119074.

Luteinizing hormone (LH) plays an important role in the gametogenesis in both sexes by promoting the production of sex steroid hormones in the testes and ovaries. We previously described a genetic variant (V) of LH resulted from a mutation (G1502A) in the LH beta-subunit gene, causing the glycine102serine change in the protein hormone. This variant was subsequently found to be associated with both male and female infertility. In this study, we determined the functional aspect of this LH variant in vitro. Site-directed mutagenesis was employed to construct the V-LH beta-subunit gene. Bioactivities of V-LH expressed in Chinese hamster ovary (CHO) cells cotransfected with the V-beta-subunit and native alpha-subunit genes were compared to those of wild-type (WT) LH. The amino acid replacement did not result in the change of efficacy of alpha- and beta-subunit dimerization of the hormone. However, V-LH had significantly lower receptor-binding activity (P<0.001) and lower biopotency for progesterone production (P<0.001) than WT-LH at the higher concentrations of LH. Considering the latter and its known association with both male and female infertility, it is suggested that the V-LH may be a contributing factor to the pathogenesis of infertility in the carriers of this variant.

online pharmacy ref. source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12189497&dopt=Abstract

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