Kegg Pathway: Biosynthesis of steroids

J Nutr Sci Vitaminol (Tokyo). 2008 Jun; 54(3): 210-4
Kobayashi M, Hamada T, Goto H, Imaizumi K, Ikeda I

Effects of dietary unesterified plant sterols and plant sterol oleates and stearates on absorption and metabolism of cholesterol were compared in rats fed a cholesterol-supplemented diet. Fecal excretion of neutral steroids (cholesterol plus coprostanol) in rats fed unesterified plant sterols or plant sterol oleates was significantly higher than in those fed the control diet or plant sterol stearates. Deposition of cholesterol in the liver was significantly lower in rats fed unesterified plant sterols or plant sterol oleates than in those fed the control diet or plant sterol stearates. No significant difference was observed in fecal excretion of cholesterol plus coprostanol and hepatic cholesterol concentration between unesterified plant sterols and plant sterol oleates. Unesterified plant sterols were significantly more effective to reduce lymphatic recovery of radiolabeled cholesterol given to the stomach than plant sterol oleates. Although our observations suggest a possibility that unesterified plant sterols are potentially more effective to inhibit cholesterol absorption than plant sterol oleates in rats, difference in the activity is substantially small between these two forms of plant sterols.

steroids. 2008 Jun 26;
Hanet N, Lancon A, Delmas D, Jannin B, Chagnon MC, Cherkaoui-Malki M, Latruffe N, Artur Y, Heydel JM

In order to provide a global analysis of the effects of endocrine disruptors on the hormone cellular bioavailability, we combined 17beta-estradiol (E2) cellular flow studies with real-time PCR and Western blot expression measurements of genes involved in the hormone metabolism and excretion. Three endocrine disruptors commonly found in food were chosen for this study, which was conducted in the estrogen receptor (ER) negative hepatoblastoma HepG2 cell line: bisphenol A (BPA), genistein (GEN) and resveratrol (RES). We showed that 24h after a single dose treatment with genistein, resveratrol or bisphenol A, the expression of ATP-binding cassette transporters (the multidrug resistance or MDR, and the multidrug resistance associated proteins or MRP) uridine diphosphate-glucuronosyltransferases (UGT) and/or sulfotransferases (ST) involved in 17beta-estradiol elimination process were significantly modulated and that 17beta-estradiol cellular flow was modified. Resveratrol induced MDR1 and MRP3 expressions, bisphenol A induced MRP2 and MRP3 expressions, and both enhanced 17beta-estradiol efflux. Genistein, on the other hand, inhibited ST1E1 and UGT1A1 expressions, and led to 17beta-estradiol cellular retention. Thus, we demonstrate that bisphenol A, genistein and resveratrol modulate 17beta-estradiol cellular bioavailability in HepG2 and that these modulations most probably involve regulations of 17beta-estradiol phase II and III metabolism proteins. Up to now, the estrogenicity of environmental estrogenic pollutants has been based on the property of these compounds to bind to ERs. Our results obtained with ER negative cells provide strong evidence for the existence of ER-independent pathways leading to endocrine disruption.

Cesk Fysiol. 2008; 57(1): 24-32
Holecek V, Rokyta R, Vlasák R

Antioxidants and trace elements are using by hundreds millions of people. Effective are especially mixtures of antioxidants. Usually is declared only the composition of the tablets, but nowadays it is not satisfactory. Substantial is how much of the antioxidants is absorbed and where, how it increases the antioxidant capacity in the blood, which effect it has, the stability of them and who, how much, which and when they are to be used. It is also very important which antioxidants during the detoxication of free radicals react first and therefore they are soon exhausted and whether at all or how quickly can they be reduced back to an active component. In aging the antioxidant capacity decreases, it is influenced by the season, all of factors are to be taken in account. The absorption and the effect are influenced by the state of gastrointestinal tract, including the microbiological flora, pH, the size of the molecules, sometimes by partial oxygen tension in the blood. Free radicals are generated mostly after a load and therefore it is suitable to have the antioxidants capacity on a high level, it is possible to increase it during the load and it is recommended the administration of them after the load. Some authors recommend low doses of antioxidants five times a day. In some diseases the antioxidants are effluenced from the tissues to the blood and then there is a defficit in tissues of them. Important are the interferences during the absorption, their metabolism in organism; it may decrease their level or increase their effectivness, the metabolism can infuence to which tissues are the antioxidants deposited, and how long will stay the increased level of antioxidant capacity. The speed of elimination by urine and stool is also important. It is useful to know from which and how much of isomers the antioxidant is composed, because the single isomer may have a different effect. The origin of antioxidants is important, as natural antioxidants are usually more effective than the sythetic ones. The toxicity of the substances should not to be neglected. Storing of antioxidants sometimes deteriorate them, or sometimes they are contaminated by anabolic steroids. Some substances like phytates can bind them and so decrease their bioavavilability. Lipid soluble substances need lipids in the diet, some antioxidants are differently absorbed from different sources of nutrition. Genetic equipment is important as well. It is apparent that the administration of antioxidants and trace elements is not simple and that the informations of commercial preparates is usually not sufficient, probably in the future at least may be mentioned total antioxidant capacity.

Endocr Regul. 2008 Jun; 4(2): 69-75
Shehata M, A M

Objective. Since it is well known that estrogen deficiency or ovariectomy (OVX) results in a reduction of sexual steroids and increased prevalence of cardiovascular diseases (CVD), it was aimed to assess the benefits of hormone replacement therapy (HRT) alone or together with antioxidant vitamins (E and C) for the protection against CVD and oxidative stress. Methods. The effect of ovariectomy and HRT alone or combined with antioxidants (Antiox) on lipid metabolism, insulin sensitivity, oxidative stress, antioxidant and markers of CVD was examined in four groups of female Wistar rats of 10 animals each: Group 1 (sham operated); Group 2 (OVX); Group 3 (OVX + HRT); Group 4 (OVX + HRT + Antiox). After four weeks of treatment total cholesterol, HDL-cholesterol (HDL-C), LDL-cholesterol (LDL-C), triglycerides (TG), Apo B lipoprotein, glucose and insulin as well as malondialdehyde (MDA; as index of lipid peroxidation), oxidized LDL (ox-LDL), homocysteine level, oxidized and reduced glutathione were determined in plasma. Results. The lipid pattern of OVX rats showed a deviation from sham group in all lipid fractions and atherogenic indexes; LDL/HDL and TC/HDL. HRT group showed partial correction of these abnormalities and the antioxidant adjunct treatment significantly improved the lipid profile. OVX rats had significantly higher insulin and glucose levels compared to the sham group which was abolished by HRT and completely normalized by adjunct antioxidant treatment. HOMA was significantly decreased by HRT and showed normal value with adjunct antioxidant treatment. The oxidative stress parameters; MDA, ox-LDL and GSSG levels were increased, also homocysteine was greatly elevated in OVX rats. The HRT significantly corrected the levels of MDA, ox-LDL and GSSG while it had no effect on homocysteine and GSH. The adjunct antioxidant treatment potentiated the HRT and showed a significant correction of homocysteine and GSH levels. Conclusion. Our data suggested that adjunct antioxidant treatment together with HRT may ameliorate the cardiovascular protection and improve metabolic syndrome as well as insulin resistance in OVX rats. Further studies are warranted to elucidate the beneficial role of antioxidant treatment on cardiovascular protection of menopause women. Key words: Rats - Ovariectomy - HRT - Antioxidants - Cardiovascular diseases - Lipids - Insulin - Glucose.

Mol Cell Endocrinol. 2008 May 28;
Kostellow AB, Morrill GA

We find that completion of the first meiotic division in Rana pipiens oocytes requires the sequential action of at least two steroids: progesterone and one or more subsequent polar metabolites of progesterone. Progesterone binding in vitro to oocyte surface receptors increases during the first 4-5h of exposure, followed by internalization of plasma membrane together with membrane-bound progesterone over the next hour. The internalized progesterone is metabolized to highly polar polyhydroxylated steroid(s) prior to nuclear membrane disappearance at 8-9h. Polar steroids alone cannot induce meiosis, but do so in oocytes pretreated with progesterone for 1h. Similarly, the non-metabolizable progestin R5020 cannot induce meiosis but does if oocytes are subsequently exposed to polar steroids. An inhibitor of steroid alpha-reductase (4-MA) prevents both progesterone metabolism and progesterone-induced meiosis. However, meiosis does occur if 4-MA is followed by a polar steroid. Thus, progesterone binding at the oocyte surface initiates a process which requires polar progesterone metabolites for completion of the first meiotic division.

N Engl J Med. 2008 Jul 3; 359(1): 85-7
Daum RS

Endocr Regul. 2008 Mar; 42(1): 69-75
Shehata M, A M

Objective. Since it is well known that estrogen deficiency or ovariectomy (OVX) results in a reduction of sexual steroids and increased prevalence of cardiovascular diseases (CVD), it was aimed to assess the benefits of hormone replacement therapy (HRT) alone or together with antioxidant vitamins (E and C) for the protection against CVD and oxidative stress. Methods. The effect of ovariectomy and HRT alone or combined with antioxidants (Antiox) on lipid metabolism, insulin sensitivity, oxidative stress, antioxidant and markers of CVD was examined in four groups of female Wistar rats of 10 animals each: Group 1 (sham operated); Group 2 (OVX); Group 3 (OVX + HRT); Group 4 (OVX + HRT + Antiox). After four weeks of treatment total cholesterol, HDL-cholesterol (HDL-C), LDL-cholesterol (LDL-C), triglycerides (TG), Apo B lipoprotein, glucose and insulin as well as malondialdehyde (MDA; as index of lipid peroxidation), oxidized LDL (ox-LDL), homocysteine level, oxidized and reduced glutathione were determined in plasma. Results. The lipid pattern of OVX rats showed a deviation from sham group in all lipid fractions and atherogenic indexes; LDL/HDL and TC/HDL. HRT group showed partial correction of these abnormalities and the antioxidant adjunct treatment significantly improved the lipid profile. OVX rats had significantly higher insulin and glucose levels compared to the sham group which was abolished by HRT and completely normalized by adjunct antioxidant treatment. HOMA was significantly decreased by HRT and showed normal value with adjunct antioxidant treatment. The oxidative stress parameters; MDA, ox-LDL and GSSG levels were increased, also homocysteine was greatly elevated in OVX rats. The HRT significantly corrected the levels of MDA, ox-LDL and GSSG while it had no effect on homocysteine and GSH. The adjunct antioxidant treatment potentiated the HRT and showed a significant correction of homocysteine and GSH levels. Conclusion. Our data suggested that adjunct antioxidant treatment together with HRT may ameliorate the cardiovascular protection and improve metabolic syndrome as well as insulin resistance in OVX rats. Further studies are warranted to elucidate the beneficial role of antioxidant treatment on cardiovascular protection of menopause women. Key words: Rats - Ovariectomy - HRT - Antioxidants - Cardiovascular diseases - Lipids - Insulin - Glucose.

Intern Med. 2008; 47(13): 1245-9
Kageyama K, Naraoka M, Sakihara S, Ikeda H, Sano T, Suda T

We describe a rare and interesting progressive case of lymphocytic hypophysitis accompanied later by paresis of the left abducens nerve. A 42-year-old woman was diagnosed as having lymphocytic hypophysitis accompanied by diabetes insipidus and hypopituitarism. She had no symptoms of visual disturbance at that time. She was not treated with steroids because she is a carrier of the hepatitis B virus. Later, in 2006, she complained of progression of symptoms and double vision for a few months. Her pituitary gland showed further enlargement. The patient was diagnosed as having progressive lymphocytic hypophysitis accompanied by paresis of the left abducens nerve, which was subsequently confirmed by biopsy. The progression of lymphocytic hypophysitis in patients not receiving steroid therapy should be carefully monitored.

Ann N Y Acad Sci. 2008; 1129: 96-104
Yanagihara N, Toyohira Y, Shinohara Y

We report here the effects of estrogens and phytoestrogens on catecholamine signaling in cultured bovine adrenal medullary cells used as a model of catecholaminergic neurons in the brain. Treatment of the cells for 20 min with 17beta-estradiol (E(2)) (0.3-100 nM) or phytoestrogens such as daidzein (0.01-1.0 microM), a soy isoflavone, and resveratrol (0.1-1.0 microM), a grape polyphenol, stimulated (14)C-catecholamine synthesis from [(14)C]tyrosine, which was associated with the activation of tyrosine hydroxylase. The stimulatory effect of E(2) and phytoestrogens was not inhibited by ICI182,780, a nuclear estrogen receptor inhibitor, but abolished by U0126, an inhibitor of extracellular signal-regulated kinase1/2 (ERK1/2) kinase. E(2) enhanced the phosphorylation of ERK1/2. The plasma membrane isolated from the adrenal medulla showed two classes of specific binding sites of [(3)H]E(2). Resveratrol and daidzein at high concentrations (> or =1.0 microM) inhibited catecholamine secretion induced by various secretagogues. The present findings suggest that estrogens and phytoestrogens most likely stimulate catecholamine synthesis via estrogen receptors in the plasma membrane, but in high concentrations phytoestrogens inhibit catecholamine secretion induced by secretagogues in adrenal medullary cells, and probably in brain neurons.

Ann N Y Acad Sci. 2008; 1129: 55-60
Sakuma Y

Rodents identify a mating partner by using olfactory cues. Female rats in estrus spend a longer time sniffing odors of sexually active males when physical contacts are hampered. Sexually active males are attracted by odors of receptive females. The preference in either sex disappears when the subjects are gonadectomized, an effect reversible by supplement with estrogen or testosterone. Thus, circulating sex steroids determine the odor preference in both sexes. In both sexes, olfactory cues get to the basal forebrain; this area includes the preoptic area (POA), substantia innominata and accumbens, structures with estrogen receptor-positive neurons. In estrous females, neurons in the POA are activated during precopulatory motivational behavior. Lesion in this area practically eliminates sexual preference and diminishes the motivation. An increase in locomotion in females in estrus, which apparently depends on estrogen-sensitive POA projections to the midbrain locomotor region, has been considered to embody enhanced sexual motivation.

steroids. 2008 May 21;
Raff H, Sluss PM

In order to standardize and harmonize testosterone measurement, it is vital to identify and minimize pre-analytical error as well as standardize them when developing reference intervals. These pre-analytic issues can be separated into technical and biological factors. Technical factors to address are the type of sample (serum vs. plasma), the type of collection tube, and the processing, storage, and handling of the samples. Biological issues include addressing the age of the subject, the time of day and month the sample is drawn, and all of the possible interfering drugs the subject may be taking. We recommend that great attention be paid to these pre-analytical issues before the assay methodologies are harmonized.

Transplant Proc. 2008 Jun; 40(5): 1566-71
Benedini S, Ruffini E, Terruzzi I, Mancuso M, Luzi L

BACKGROUND: This study examined the metabolic effects of lung transplantation in patients with end-stage respiratory failure on low dose of steroids for immunosuppressive therapy. METHODS: We examined 6 patients, including 2 women and 4 men of overall mean age 53 +/- 15 years and age at transplantation 34 +/- 12 months, receiving cyclosporine 5.73 +/- 1.43 mg/kg/d or tacrolimus (FK 506) 4.67 +/- 0.58 mg/d, azathioprine 0.47 +/- 0.29 mg/kg/d, and prednisone 8.25 mg/d for comparison with 6 healthy subjects, who were selected to be comparable to the recipients in terms of anthropometric features and age. A euglycemic hyperinsulinemic clamp (1 mU/kg/min) associated with infusion of glucose and leucine isotopes was performed with indirect calorimetry. RESULTS: Lung transplanted patients showed postabsorptive leucine and free fatty acid metabolism similar to controls. In contrast, there was peripheral insulin resistance with respect to glucose metabolism namely, higher values of glucose and insulin vs controls (P < .03 and P < .02, respectively). During the clamp the metabolic picture was characterized by a relative insulin resistance with respect to glucose metabolism (P = .07). Lipid and protein metabolism in the basal and insulin-stimulated conditions were similar to the control group. CONCLUSIONS: In the basal condition insulin resistance is evident with respect to glucose metabolism. The metabolic picture in lung transplanted patients on low-dose steroid therapy was characterized by normal insulin-stimulated glucose, leucine, and free fatty acid metabolism. The minimal metabolic alterations in these patients were not due to transplantation itself but probably mainly attributable to immunosuppressive therapy.

Vet Pathol. 2008 Jul; 45(4): 439-42
Wagner S, Kiupel M, Peterson RA, Heikinheimo M, Wilson DB

Whereas the adrenal glands of healthy ferrets produce only limited amounts of androgenic steroids, adrenocortical neoplasms that arise in neutered ferrets typically secrete androgens or their derivative, estrogen. The 17,20-lyase activity of cytochrome P450 17alpha-hydroxylase/17,20-lyase (P450c17) must increase to permit androgen Biosynthesis in neoplastic adrenal tissue. We screened ferret adrenocortical tumor specimens for expression of cytochrome b(5) (cyt b(5)), an allosteric regulator that selectively enhances the 17,20-lyase activity of P450c17. Cyt b(5) immunoreactivity was evident in 24 of 25 (96%) adrenocortical adenomas/carcinomas from ferrets with signs of ectopic sex steroid production. Normal adrenocortical cells lacked cyt b(5), which may account for the low production of adrenal androgens in healthy ferrets. Other markers characteristic of gonadal somatic cells, such as luteinizing hormone receptor, aromatase, and GATA4, were coexpressed with cyt b(5) in some of the tumors. We concluded that cyt b(5) is upregulated during gonadectomy-induced adrenocortical neoplasia and is a marker of androgen synthetic potential in these tumors.

J Chromatogr B Analyt Technol Biomed Life Sci. 2008 Jun 14;
Sirén H, Seppänen-Laakso T, Orešič M

The aim of this study was to develop a method for comprehensive profiling of metabolites involved in mammalian steroid metabolism. The study was performed using the partial filling micellar electrokinetic chromatography (PF-MEKC) technique for determination of endogenous low-hydrophilic steroids. The detection techniques in capillary electrophoresis were UV absorption and electrospray mass spectrometry (ESI-MS). Thirteen steroids were included in the method development, and the selected were metabolites involved in major pathways of steroid Biosynthesis. Although only eight of them could be separated and detected with UV, they could be identified by ESI-MS using selected ion monitoring (SIM) technique. Tandem MS spectra were also collected. UV detection was more sensitive than MS due to better separation of compounds and the selective signal sensitivity. The lowest limits of detection were 10-100ng/mL for cortisone, corticosterone, hydrocortisone and testosterone. The other steroids could be detected at 500-1000ng/mL. The identification of cortisone, corticosterone, hydrocortisone, estrogen and testosterone were made in patient urine samples and their concentrations were 1-40mug/L.

Proc Natl Acad Sci U S A. 2008 Jun 3; 105(22): 7893
Schekman R

Eur Rev Med Pharmacol Sci. 2008 Mar-Apr; 12(2): 83-8
Pérez-Castrillón JL, Abad L, Vega G, Sanz-Cantalapiedra A, García-Porrero M, Pinacho F, Dueñas A

OBJECTIVE: The aim of this paper is to evaluate the effect of atorvastatin on bone mineral density in patients with acute ischemic heart disease. MATERIAL AND METHODS: Eighty-three patients (52 male and 31 female) with acute coronary syndrome were studied. They received treatment with atorvastatin using low doses (20 mg) and high doses (40 mg-80 mg). Initial and final cholesterol, triglyceride, calcium, phosphorus, 25-hydroxyvitamin D were obtained from every patient. Spine and hip bone mineral density were performed at the beginning and one year later. RESULTS: Atorvastatin treatment increases vitamin D (33%, p = 0.007) and decreases the individuals with vitamin D insufficiency. Bone mineral density increased in the spine (1.31%, p = 0.02), but it was significant only in male and patients presenting vitamin D levels higher than 30 nmol/l. CONCLUSION: Atorvastatin has a beneficial effect on bone metabolism in patients with acute ischemic heart disease (mainly males) by incrementing bone mineral density in which vitamin D levels are required to be higher than 30 nmol/l for the drug to be effective.

Arch Intern Med. 2008 Jun 23; 168(12): 1340-9
Dobnig H, Pilz S, Scharnagl H, Renner W, Seelhorst U, Wellnitz B, Kinkeldei J, Boehm BO, Weihrauch G, Maerz W

BACKGROUND: In cross-sectional studies, low serum levels of 25-hydroxyvitamin D are associated with higher prevalence of cardiovascular risk factors and disease. This study aimed to determine whether endogenous 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels are related to all-cause and cardiovascular mortality. METHODS: Prospective cohort study of 3258 consecutive male and female patients (mean [SD] age, 62 [10] years) scheduled for coronary angiography at a single tertiary center. We formed quartiles according to 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels within each month of blood drawings. The main outcome measures were all-cause and cardiovascular deaths. RESULTS: During a median follow-up period of 7.7 years, 737 patients (22.6%) died, including 463 deaths from cardiovascular causes. Multivariate-adjusted hazard ratios (HRs) for patients in the lower two 25-hydroxyvitamin D quartiles (median, 7.6 and 13.3 ng/mL [to convert 25-hydroxyvitamin D levels to nanomoles per liter, multiply by 2.496]) were higher for all-cause mortality (HR, 2.08; 95% confidence interval [CI], 1.60-2.70; and HR, 1.53; 95% CI, 1.17-2.01; respectively) and for cardiovascular mortality (HR, 2.22; 95% CI, 1.57-3.13; and HR, 1.82; 95% CI, 1.29-2.58; respectively) compared with patients in the highest 25-hydroxyvitamin D quartile (median, 28.4 ng/mL). Similar results were obtained for patients in the lowest 1,25-dihydroxyvitamin D quartile. These effects were independent of coronary artery disease, physical activity level, Charlson Comorbidity Index, variables of mineral metabolism, and New York Heart Association functional class. Low 25-hydroxyvitamin D levels were significantly correlated with variables of inflammation (C-reactive protein and interleukin 6 levels), oxidative burden (serum phospholipid and glutathione levels), and cell adhesion (vascular cell adhesion molecule 1 and intercellular adhesion molecule 1 levels). CONCLUSIONS: Low 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels are independently associated with all-cause and cardiovascular mortality. A causal relationship has yet to be proved by intervention trials using vitamin D.

steroids. 2008 Oct; 73(11): 1187-96
Gong R, Morris DJ, Brem AS

Vascular tissue expresses two isoforms of the enzyme 11beta-Hydroxysteroid dehydrogenase, 11beta-HSD1 and 11beta-HSD2. These enzymes are responsible for the local metabolism of endogenous glucocorticoids (GCs). 11beta-HSD1 deactivates GCs to their 11keto metabolites or transforms inert 11keto metabolites back to active GCs. Although, bi-directional, vascular 11beta-HSD1 favors reactivation (reductase) over the deactivation (dehydrogenase) reaction, 11beta-HSD2 only functions as a dehydrogenase. GC deactivation by enhanced 11beta-HSD2 dehydrogenase activity or by impaired 11beta-HSD1 reductase activity correlates with lower vascular resistance. These studies were designed to demonstrate the existence and regulation of these isoforms in vascular endothelial cells and to determine whether the expression varied by species and locale. Western blots were prepared from pre-confluent and confluent cultures of human umbilical vein endothelial cells (HUVEC). 11beta-HSD1 was clearly expressed while 11beta-HSD2 was much less prominent. Cultured rat aortic and bovine glomerular endothelial cells showed a similar pattern. Using immunohistochemistry, endothelial cells from human and mouse artery preparations clearly demonstrated 11beta-HSD1. In separate experiments, pre-confluent growing HUVEC expressed more 11beta-HSD1 compared to confluent cells. Serum-deprived growth-retarded HUVEC expressed significantly less 11beta-HSD1. The enhanced expression of 11beta-HSD1 was also observed 24h following a scratch "injury" to the culture plates. Changes in 11beta-HSD1 with growth and during repair occurred at the transcription level. Thus, 11beta-HSD1 protein expression predominates in endothelial cells and varies during periods of growth.

Polim Med. 2007; 37(4): 59-64
Szcześniak M, Kubis AA, Pluta J

Studies on the effect of hydrophilic gel composition on pharmaceutical availability of prednisolone complexed with beta-cyklodextrin at P:beta-CD ratios 1:1 and 1:2 revealed that the half-release times were shortened and differentiated depending on the substances added hydrogel to propylene glycol, dimethylacetamide and polysorbate 20 in comparison to preparations containing non-complexed active substance.

Pathophysiology. 2008 Jun 20;
Olatunji LA, Soladoye AO

Estrogen-progestogen oral contraceptive (OC) use is associated with abnormal lipid metabolism, impaired glucose tolerance and high prevalence of vascular complications. OC use has been shown to alter the requirements for folic acid. Therefore, the aim of the present study was to clarify the influence of dietary folic acid on OC-induced impaired glucose tolerance and abnormal plasma lipid profile in female Sprague-Dawley rats. Vehicle-treated and OC-treated rats were fed for 6 weeks with a control diet (750mug folic acid/kg diet) while OC-treated folic acid deficient (FD) rats were fed for 6 weeks with a folic acid-deficient diet (250mug folic acid/kg diet). OC receiving rats were treated with a combination of OC steroids (ethinyl estradiol and norgestrel) by oral gavage. OC treatment resulted in rats receiving folic acid deficient diet in impaired glucose tolerance, decreased high-density lipoprotein (HDL)-cholesterol and increased low-density lipoprotein (LDL)-cholesterol when compared with control rats. However, OC treatment did not result in impaired glucose tolerance or disturbed plasma lipid profile in rats receiving the same folic acid level as the controls. OC treatment led to significant decreases in plasma levels of 17beta-estradiol and testosterone in both groups. OC administration in rats with folic acid deficient diet significantly lower HDL-cholesterol and higher LDL-cholesterol levels while plasma levels of 17beta-estradiol and testosterone were similar in both OC-treated groups. Conclusion: These results demonstrate impaired glucose tolerance and disturbed plasma lipid profile induced by OC treatment in folic acid deficient rats and suggest that inadequate folic acid intake might contribute to increased cardiovascular risk during OC use that could be prevented by proper oral folic acid intake.