Biomedical subjects

K Ebihara

Publications and source records attributed to K Ebihara.

At least 19 recordsLinked to original sources

PubMed2006

Expression of the gene for a membrane-bound fatty acid receptor in the pancreas and islet cell tumours in humans: evidence for GPR40 expression in pancreatic beta cells and implications for insulin secretion.

AIMS/HYPOTHESIS: G protein-coupled receptor 40 (GPR40) is abundantly expressed in pancreatic beta cells in rodents, where it facilitates glucose-induced insulin secretion in response to mid- to long-chain fatty acids in vitro. However, GPR40 gene expression in humans has not been fully investigated, and little is known about the physiological and pathophysiological roles of GPR40 in humans. The aim of this study, therefore, was to examine GPR40 expression and its clinical implications in humans. METHODS: GPR40 mRNA expression in the human pancreas, pancreatic islets and islet cell tumours was analysed using TaqMan PCR. RESULTS: GPR40 mRNA was detected in all human pancreases collected intraoperatively. It was enriched approximately 20-fold in isolated islets freshly prepared from the pancreases of the same individuals. The estimated mRNA copy number for the GPR40 gene in pancreatic islets was comparable to those for genes encoding sulfonylurea receptor 1, glucagon-like peptide 1 receptor and somatostatin receptors, all of which are known to be expressed abundantly in the human pancreatic islet. A large amount of GPR40 mRNA was detected in insulinoma tissues, whereas mRNA expression was undetectable in glucagonoma or gastrinoma. The GPR40 mRNA level in the pancreas correlated with the insulinogenic index, which reflects beta cell function (r=0.82, p=0.044), but not with glucose levels during the OGTT, the insulin area under the OGTT curve or the index for the homeostasis model assessment of insulin resistance (HOMA-IR). CONCLUSIONS/INTERPRETATION: The present study provides evidence for GPR40 gene expression in pancreatic beta cells and implicates GPR40 in insulin secretion in humans.

Adult↗

PubMed2004

Serum leptin level is a regulator of bone mass.

Leptin is a powerful inhibitor of bone formation in vivo. This antiosteogenic function involves leptin binding to its receptors on ventromedial hypothalamic neurons, the autonomous nervous system and beta-adrenergic receptors on osteoblasts. However, the mechanisms whereby leptin controls the function of ventromedial hypothalamic antiosteogenic neurons remain unclear. In this study, we compared the ability of leptin to regulate body weight and bone mass and show that leptin antiosteogenic and anorexigenic functions are affected by similar amounts of leptin. Using a knock-in of LacZ in the leptin locus, we failed to detect any leptin synthesis in the central nervous system. However, increasing serum leptin level, even dramatically, reduced bone mass. Conversely, reducing serum-free leptin level by overexpressing a soluble receptor for leptin increased bone mass. Congruent with these results, the high bone mass of lipodystrophic mice could be corrected by restoring serum leptin level, suggesting that leptin is an adipocyte product both necessary and sufficient to control bone mass. Consistent with the high bone mass phenotype of lipodystrophic mice, we observed an advanced bone age, an indirect reflection of premature bone formation, in lipodystrophic patients. Taken together, these results indicate that adipocyte-derived circulating leptin is a determinant of bone formation and suggests that leptin antiosteogenic function is conserved in vertebrates.

Animals↗

PubMed2003

Leptin as an adjunct of insulin therapy in insulin-deficient diabetes.

AIMS/HYPOTHESIS: The purpose of this study was to assess the therapeutic implication of leptin in insulin-deficient diabetes. METHODS: Insulin-deficient diabetes was induced by streptozotocin (STZ) in transgenic skinny mice overexpressing leptin. Plasma concentrations of glucose, insulin, and leptin were measured. The effects on body weight, food intake, and hypothalamic gene expressions were analyzed. After diabetes was induced, graded doses of insulin ranging from 0.4 to 51.2 mU.g(-1).day(-1) were injected. Co-administration of leptin and insulin was also carried out using osmotic pumps. RESULTS: After STZ injection, both transgenic and non-transgenic littermates developed marked hyperglycaemia as a result of severe hypoinsulinaemia [termed diabetic transgenic skinny mice overexpressing leptin (diabetic TGM) and diabetic non-transgenic littermates (diabetic WT) respectively], although diabetic TGM were more sensitive to exogenously administered insulin than diabetic WT. Diabetic WT were hypoleptinaemic and hyperphagic relative to non-diabetic WT, whereas diabetic TGM, which remained hyperleptinaemic, were less hyperphagic than diabetic WT. After STZ injection, hypothalamic expressions of orexigenic and anorexigenic peptide mRNAs were up-regulated and down-regulated, respectively, in diabetic WT, whereas they were unchanged in diabetic TGM. Diabetic TGM became normoglycaemic, when treated with insulin at such doses that did not improve hyperglycaemia in diabetic WT. We found that a sub-threshold dose of insulin that does not affect glucose homeostasis is effective in improving the diabetes in normal mice rendered diabetic by STZ injection, when combined with leptin. CONCLUSIONS/INTERPRETATION: This study suggests that leptin could be used as an adjunct of insulin therapy in insulin-deficient diabetes, thereby providing an insight into the therapeutic implication of leptin as an anti-diabetic agent.

Agouti-Related Protein↗

PubMed2003

Anti-obesity and anti-diabetic effects of brain-derived neurotrophic factor in rodent models of leptin resistance.

OBJECTIVE: Obesity in rodents and humans is mostly associated with elevated plasma leptin concentrations, suggesting a new pathological concept of 'leptin resistance'. We have demonstrated that brain-derived neurotrophic factor (BDNF) can improve obesity and diabetes of C57BL/KsJ db/db (db/db) mice. In this study, we investigated whether or not BDNF is effective in two different models of leptin resistance, an acquired model and a genetic model. DESIGN: C57BL/6J mice rendered obese by consumption of a high-fat diet (diet-induced obesity (DIO) mice) were used as an acquired model and lethal yellow agouti mice (KKA(y) mice) as a genetic model of leptin resistance. Food intake and glucose metabolism were studied after acute or repetitive administration of BDNF. RESULTS: Intraperitoneal administration of BDNF (10 mg/kg, twice/day) significantly reduced cumulative food intake of DIO and KKA(y) mice, whereas they were unresponsive to leptin administration. Repetitive subcutaneous administration of BDNF (10 mg/kg daily for 6 days) reduced food intake and improved impaired glucose tolerance in DIO mice. Pair feeding of vehicle-treated DIO mice with the same amount of chow consumed by the BDNF-treated group did not improve the impaired glucose homeostasis, indicating that the antidiabetic effect is not due to decreased food intake. We also observed that BDNF is effective in improving obesity and diabetes of KKA(y) mice. CONCLUSION: This study demonstrated antiobesity and antidiabetic effects of BDNF in two different models of leptin resistance, thereby suggesting the therapeutic potential of BDNF in the treatment of leptin-resistant obesity and diabetes.

Animals↗

PubMed2001

Influence of age and ovariectomy on the hypocholesterolemic effects of dietary taurine in rats fed a cholesterol-free diet.

The effects of taurine feeding on plasma cholesterol concentrations and fecal bile acid excretion were examined in young and aged male and female rats (5 weeks and 10 months old respectively), the latter either ovariectomized (ovx) or sham-operated. The rats were fed a cholesterol-free diet (C diet) or a cholesterol-free taurine-supplemented diet (T diet; C + 5% taurine) for 28 days. In males, plasma cholesterol concentrations and fecal bile acid excretion were higher and lower, respectively, in aged rats than in young rats, but were not affected by feeding with the T diet. In female rats, plasma cholesterol concentrations were higher in aged rats than in young rats and higher in ovx-rats than in sham-operated rats. In contrast to male rats, plasma cholesterol concentrations were lower in female rats fed the T diet than in those fed the C diet. Plasma cholesterol concentrations were increased in aged ovx-rats, but decreased by feeding with the T diet. Fecal bile acid excretion was higher in rats fed the T diet than in those fed the C diet. Thus, these data indicate that the hypocholesterolemic effect of taurine is greater in aged rats than in young rats.

Journal Article↗

PubMed2001

Yeast [PSI+] "prions" that are crosstransmissible and susceptible beyond a species barrier through a quasi-prion state.

The yeast [PSI(+)] element represents an aggregated form of release factor Sup35p and is inherited by a prion mechanism. A "species barrier" prevents crosstransmission of the [PSI(+)] state between heterotypic Sup35p "prions." Kluyveromyces lactis and Yarrowia lipolytica Sup35 proteins, however, show interspecies [PSI(+)] transmissibility and susceptibility and a high spontaneous propagation rate. Cross-seeding was visualized by coaggregation of differential fluorescence probes fused to heterotypic Sup35 proteins. This coaggregation state, referred to as a "quasi-prion" state, can be stably maintained as a heritable [PSI(+)] element composed of heterologous Sup35 proteins. K. lactis Sup35p was capable of forming [PSI(+)] elements not only in S. cerevisiae but in K. lactis. These two Sup35 proteins contain unique multiple imperfect oligopeptide repeats responsible for crosstransmission and high spontaneous propagation of novel [PSI(+)] elements.

Candida↗

PubMed2001

Immunohistochemical characterisation of Fos-positive cells in brainstem monoaminergic nuclei following intracranial self-stimulation of the medial forebrain bundle in the rat.

Fos immunostaining was used as a marker of neuronal activity following intracranial self-stimulation (ICSS) of the medial forebrain bundle (MFB) in the rat, and was combined with immunostaining for tyrosine hydroxylase (TH), serotonin (5-HT), gamma-aminobutyric acid (GABA), or NR1 (one of the glutamate N-methyl- D-aspartate receptor subunits) for purposes of neurochemical identification. ICSS induced a significant but different degree of increase in the number of Fos-immunopositive (Fos+) cells in the six brainstem monoaminergic nuclei examined, which included the ventral tegmental area (VTA), substantia nigra pars compacta (SNc), dorsal raphe nucleus (DR), median raphe nucleus (MR), locus coeruleus (LC), and A7 noradrenaline cells. Densely labelled Fos+ cells were observed in the LC following ICSS, and many of these Fos+ cells were colocalized with TH. Similarly, many of Fos+ cells in the A7 and DR/MR were colocalized with TH and 5-HT, respectively. By contrast, a smaller number of Fos+ cells was detected in the VTA and SNc following the ICSS, and in these regions the majority of Fos+ cells were not colocalized with TH. Although results among regions quantitatively differed, the ICSS induced a significant increase in the number of double-labelled cells (GABA+/Fos+ or NR1+/Fos+) in all of the VTA, DR, and LC, in which the ICSS produced an ipsilaterally weighted increase in Fos-like immunoreactivity. These results suggest that ICSS of the MFB induces differential Fos expression within monoaminergic and GABAergic neurons in brainstem monoaminergic nuclei under modulation by glutamatergic afferents.

Animals↗

PubMed2001

Heat moisture treatment of high amylose cornstarch increases its resistant starch content but not its physiologic effects in rats.

To examine whether the physiologic effects of high amylose cornstarch (HACS) are affected by gelatinization or heat moisture treatment, male rats were fed for 21 d a fiber-free purified diet containing 40 g/100 g gelatinized normal cornstarch (G-CS), HACS, gelatinized high amylose cornstarch (G-HACS) or heat moisture-treated HACS (HMCS). Dietary fiber (DF) content in G-HACS was 87% lower than that in HACS. The apparent starch and protein digestibilities were higher in the G-HACS group than in the HACS group. Fecal wet weight and fecal bile acid excretion were lower in the G-HACS group than in the HACS group. The cecal tissue weight, cecal surface area, cecal content weight and cecal pH were lower in the G-HACS group than in the HACS group. The cecal n-butyric acid and succinic acid concentrations were higher and lower, respectively, in the G-HACS group than in the HACS group. The plasma cholesterol and triacylglycerol concentrations did not differ between the G-HACS group and the HACS group. On the other hand, the DF content in HMCS was 330% higher than that in HACS, but the HMCS and HACS groups generally did not differ except in cecal surface area. Dietary starch did not affect fecal moisture, fecal neutral sterol (cholesterol + coprostanol) excretion, liver cholesterol level, total short-chain fatty acid (SCFA) concentration or apparent Ca, Fe, Mg and Zn absorptions. These results show that the heat moisture treatment of HACS for the most part does not alter its physiologic effects despite the greater DF content.

Amylose↗

PubMed2001

Hydroxypropyl-distarch phosphate from Tapioca starch reduces zinc and iron absorption, but not calcium and magnesium absorption, in rats.

Male rats were fed a fiber-free, purified diet containing either gelatinized tapioca starch that was not modified chemically (TS, 50 g/kg diet) or gelatinized chemically modified tapioca starch (CMS, 50 g/kg) for 21 d. TS was used as the control. The six kinds of gelatinized hydroxypropyl distarch phosphate (HDP) from tapioca with two different degrees of substitution (DS) and three different degrees of cross-linking (DC) were used as CMS sources. The wet weight and moisture of fecal output of the rats fed HDP with higher DS were 100 and 20% greater than that in the control rats, respectively. The weights of cecal wall and cecal contents were also 30 and 50% higher in the rats fed HDP with higher DS than those in the control rats. The pH of the cecal contents was more acidic in the rats fed HDP with higher DS than that in the control rats. Fecal excretion of bile acids was 40% higher in the rats fed HDP with higher DS than in the control rats. These effects of HDP were only slightly affected by the DC. The plasma cholesterol concentration was 16% lower in the rats fed HDP with higher DS and highest DC than in the control rats. The concentrations of liver lipids and plasma triglycerides and the cecal pool of organic acids were not affected by diet. The apparent absorptions of Ca and Mg were not affected by diet, but those of Zn and Fe were 75 and 70% lower in the rats fed HDP with higher DS than in the control rats. These results suggest that the physiological effects of HDP depend on the DS but not on the DC.

Animals↗

PubMed2001

Decreased triglyceride-rich lipoproteins in transgenic skinny mice overexpressing leptin.

Leptin is an adipocyte-derived circulating satiety factor with a variety of biological effects. Evidence has accumulated suggesting that leptin may modulate glucose and lipid metabolism. In the present study, we examined lipid metabolism in transgenic skinny mice with elevated plasma leptin concentrations. The plasma concentrations of triglycerides and free fatty acids in transgenic skinny mice were 71.5 (P < 0.01) and 89.1% (P < 0.05) of those in their nontransgenic littermates, respectively. Separation of plasma into lipoprotein classes by ultracentrifugation revealed that very low density lipoprotein-triglyceride concentrations were markedly reduced in transgenic skinny mice relative to the controls. The clearance of triglycerides estimated by a fat-loading test was enhanced in transgenic skinny mice; the triglyceride concentration in transgenic skinny mice 3 h after fat loading was 39.7% (P < 0.05) of that of their nontransgenic littermates. Postheparin plasma lipoprotein lipase activity increased 1.4-fold (P < 0.05) in transgenic skinny mice. Our data demonstrated a significant reduction in plasma triglyceride concentrations, accompanied by increased lipoprotein lipase activity in transgenic skinny mice overexpressing leptin, suggesting that leptin plays a role in long-term triglyceride metabolism.

Animals↗

PubMed2001

Ghrelin, an endogenous growth hormone secretagogue, is a novel orexigenic peptide that antagonizes leptin action through the activation of hypothalamic neuropeptide Y/Y1 receptor pathway.

Ghrelin, an endogenous ligand for growth hormone secretagogue (GHS) receptor originally isolated from the stomach, occurs in the hypothalamic arcuate nucleus and may play a role in energy homeostasis. Synthetic GHSs have activated the hypothalamic arcuate neurons containing neuropeptide Y (NPY), suggesting the involvement of NPY in some of ghrelin actions. This study was designed to elucidate the role of ghrelin in the regulation of food intake. A single intracerebroventricular (ICV) injection of ghrelin (5-5,000 ng/rat) caused a significant and dose-related increase in cumulative food intake in rats. Ghrelin (500 ng/rat) was also effective in growth hormone-deficient spontaneous dwarf rats. Hypothalamic NPY mRNA expression was increased in rats that received a single ICV injection of ghrelin (500 ng/rat) (approximately 160% of that in vehicle-treated groups, P < 0.05). The ghrelin's orexigenic effect was abolished dose-dependently by ICV co-injection of NPY Y1 receptor antagonist (10-30 microg/rat). The leptin-induced inhibition of food intake was reversed by ICV co-injection of ghrelin in a dose-dependent manner (5-500 ng/rat). Leptin reduced hypothalamic NPY mRNA expression by 35% (P < 0.05), which was abolished by ICV co-injection of ghrelin (500 ng/rat). This study provides evidence that ghrelin is an orexigenic peptide that antagonizes leptin action through the activation of hypothalamic NPY/Y1 receptor pathway.

Animals↗

PubMed2001

Transgenic overexpression of leptin rescues insulin resistance and diabetes in a mouse model of lipoatrophic diabetes.

Lipoatrophic diabetes is caused by a deficiency of adipose tissue and is characterized by severe insulin resistance, hypoleptinemia, and hyperphagia. The A-ZIP/F-1 mouse (A-ZIPTg/+) is a model of severe lipoatrophic diabetes and is insulin resistant, hypoleptinemic, hyperphagic, and shows severe hepatic steatosis. We have also produced transgenic "skinny" mice that have hepatic overexpression of leptin (LepTg/+) and no adipocyte triglyceride stores, and are hypophagic and show increased insulin sensitivity. To explore the pathophysiological and therapeutic roles of leptin in lipoatrophic diabetes, we crossed LepTg/+ and A-ZIPTg/+ mice, producing doubly transgenic mice (LepTg/+:A-ZIPTg/+) virtually lacking adipose tissue but having greatly elevated leptin levels. The LepTg/+:A-ZIPTg/+ mice were hypophagic and showed improved hepatic steatosis. Glucose and insulin tolerance tests revealed increased insulin sensitivity, comparable to LepTg/+ mice. These effects were stable over at least 6 months of age. Pair-feeding the A-ZIPTg/+ mice to the amount of food consumed by LepTg/+:A-ZIPTg/+ mice did not improve their insulin resistance, diabetes, or hepatic steatosis, demonstrating that the beneficial effects of leptin were not due to the decreased food intake. Continuous leptin administration that elevates plasma leptin concentrations to those of LepTg/+:A-ZIPTg/+ mice also effectively improved hepatic steatosis and the disorder of glucose and lipid metabolism in A-ZIP/F-1 mice. These data demonstrate that leptin can improve the insulin resistance and diabetes of a mouse model of severe lipoatrophic diabetes, suggesting that leptin may be therapeutically useful in the long-term treatment of lipoatrophic diabetes.

Animals↗

PubMed2001

[Pathology and significance of leptin resistance in obesity].

Leptin, the protein product of the ob gene, is predominantly secreted from white adipose tissue, and acts on the brain to regulate food intake, energy expenditure, and neuroendocrine function. Obese rodent and humans are mostly associated with high circulating leptin levels. These findings have led to the conclusion that obese individuals are relatively insensitive to endogenous leptin termed 'leptin resistance'. The potential sites for leptin resistance include the blood-brain-barrier transport system and the leptin signaling mechanism in leptin-responsive neurons in the hypothalamus. In this review, we describe leptin, leptin receptor, and potential hypothesis of leptin resistance.

Animals↗

PubMed2000

Soy isoflavonoid aglycons genistein and daidzein Do not increase the cytochrome P-450 content of the liver microsomes of mice.

Mice (4-week-old, male ddy) were fed four isonitrogenic diets for 21 days: purified diet (C diet); fermented soybean (400 mg of soy isoflavonoids/kg; FSB); fermented soybean extract (400 mg of soy isoflavonoid aglycones/kg; FSBE); C with indole-3 carbinol (I3C) (2500 mg of I3C/kg; I3C). The I3C and FSB diets significantly increased the cytochrome P-450 content of hepatic microsomes in comparison with the C diet, while the FSBE diet did not. Other mice were fed seven diets for 21 days: C; C with 100 mg or 200 mg of genistein, 100 mg or 200 mg of daidzein, or 100 mg of genistein + 100 mg of daidzein/kg; I3C diet. Genistein and daidzein did not change the liver cytochrome P-450 content. There was no synergistic effect of the combined feeding of genistein and daidzein. The increase in the cytochrome P-450 content with the FSB diet depends on chemicals other than genistein and daidzein. Genistein and daidzein do not induce cytochrome P-450.

Animals↗

PubMed2000

Soybean meal fermented by Aspergillus awamori increases the cytochrome P-450 content of the liver microsomes of mice.

The effect of soybean meal fermented by Aspergillus awamori on the acute lethality of acetaldehyde, pentobarbital sleeping time, and cytochrome P-450 content of the hepatic microsomes was studied in mice. Most of the daidzin and genistin in soybean meal (SBM) were converted into the respective aglycones, daidzein and genistein, by fermentation. In experiment 1, mice were fed isonitrogenic test diets with one of the following five protein sources for 28 d: casein, SBM, fermented and hot-air-dried SBM (FSBM-HD), fermented and freeze-dried SBM (FSBM-FD), or methanol-extracted FSBM-FD (FSMB-FD-R). The acute lethality of acetaldehyde in mice fed the FSBM-FD diet was significantly lower than that in mice fed the SBM, FSBM-HD, or FSBM-FD-R diet. In experiments 2 and 3, mice were fed isonitrogenic test diets with one of the following four protein sources for 28 d: casein, SBM, FSBM-FD, and FSBM-FD-R. The pentobarbital sleeping time was significantly shorter and the cytochrome P-450 content was significantly higher in the mice fed the FSBM-FD diet than the respective value in mice fed the other test diets. In experiment 4, mice were fed one of eight diets which contained different levels of aglycone obtained by varying the proportion of FSBM-FD and FSBM-FD-R, for 28 d. The cytochrome P-450 content in hepatic microsomes increased as the dietary level of isoflavonoid aglycones increased, but there was a saturation phenomenon. These results suggest that soy isoflavonoid aglycones are more potent inducers of cytochrome P-450 than isoflavonoid glycosides.

Acetaldehyde↗

PubMed2000

Pathophysiological role of leptin in obesity-related hypertension.

To explore the pathophysiological role of leptin in obesity-related hypertension, we examined cardiovascular phenotypes of transgenic skinny mice whose elevated plasma leptin concentrations are comparable to those seen in obese subjects. We also studied genetically obese KKA(y) mice with hyperleptinemia, in which hypothalamic melanocortin system is antagonized by ectopic expression of the agouti protein. Systolic blood pressure (BP) and urinary catecholamine excretion are elevated in transgenic skinny mice relative to nontransgenic littermates. The BP elevation in transgenic skinny mice is abolished by alpha(1)-adrenergic, beta-adrenergic, or ganglionic blockers at doses that do not affect BP in nontransgenic littermates. Central administration of an alpha-melanocyte-stimulating hormone antagonist causes a marked increase in cumulative food intake but no significant changes in BP. The obese KKA(y) mice develop BP elevation with increased urinary catecholamine excretion relative to control KK mice. After a 2-week caloric restriction, BP elevation is reversed in nontransgenic littermates with the A(y) allele, in parallel with a reduction in plasma leptin concentrations, but is sustained in transgenic mice overexpressing leptin with the A(y) allele, which remain hyperleptinemic. This study demonstrates BP elevation in transgenic skinny mice and obese KKA(y) mice that are both hyperleptinemic, thereby suggesting the pathophysiological role of leptin in some forms of obesity-related hypertension.

Adrenergic alpha-Antagonists↗

PubMed2000

Accelerated puberty and late-onset hypothalamic hypogonadism in female transgenic skinny mice overexpressing leptin.

Excess or loss of body fat can be associated with infertility, suggesting that adequate fat mass is essential for proper reproductive function. Leptin is an adipocyte-derived hormone that is involved in the regulation of food intake and energy expenditure, and its synthesis and secretion are markedly increased in obesity. Short-term administration of leptin accelerates the onset of puberty in normal mice and corrects the sterility of leptin-deficient ob/ob mice. These findings suggest a role for leptin as an endocrine signal between fat depots and the reproductive axis, but the effect of hyperleptinemia on the initiation and maintenance of reproductive function has not been elucidated. To address this issue, we examined the reproductive phenotypes of female transgenic skinny mice with elevated plasma leptin concentrations comparable to those in obese subjects. With no apparent adipose tissue, female transgenic skinny mice exhibit accelerated puberty and intact fertility at younger ages followed by successful delivery of healthy pups. However, at older ages, they develop hypothalamic hypogonadism characterized by prolonged menstrual cycles, atrophic ovary, reduced hypothalamic gonadotropin releasing hormone contents, and poor pituitary luteinizing hormone secretion. This study has demonstrated for the first time to our knowledge that accelerated puberty and late-onset hypothalamic hypogonadism are associated with chronic hyperleptinemia, thereby leading to a better understanding of the pathophysiological and therapeutic implication of leptin.

Adipose Tissue↗

PubMed2000

Effect of dietary soy isoflavone aglycones on the urinary 16alpha-to-2-hydroxyestrone ratio in C3H/HeJ mice.

Estradiol is metabolized through two mutually exclusive pathways. 2-Hydroxyestrone (2-OHE,) is antiestrogenic, while 16alpha-hydroxyestrone (16alpha-OHE1) is a potent estrogen. It is suggested that a high urinary 16alpha-OHE1-to-2-OHE1 rato is a biomarker of increased mammary tumor risk. Mice were fed one of the test diets for 21 days. Indole-3-carbinol (2,500 mg/kg diet) increased the cytochrome P-450 content of hepatic microsomes and liver weight and reduced the urinary 16alpha-OHE1-to-2-OHE1 ratio in comparison with the respective value in the control mice. Fermented soy extract (100, 200, or 400 mg isoflavonoid/kg diet), genistein (200 mg/kg diet), and daidzein (200 mg/kg diet) each reduced the urinary 16alpha-OHE1-to-2-OHE1 ratio without increasing the cytochrome P-450 content of hepatic microsomes or liver weight. The combination of genistein and daidzein (100 mg and 100 mg/kg diet) did not have a synergistic effect on the reduction in urinary 16alpha-OHE1-to-2-OHE1 ratio. These data suggest that the soy isoflavonoid aglycones genistein and daidzein and indole-3-carbinol each exert a cancer-preventive effect by shifting metabolism away from the production of genotoxic metabolites toward the production of inactive metabolites.

Animals↗