Papers by Octavio Pérez Luzardo
Journal of Steroid Biochemistry and Molecular Biology, 2003
Steroid-binding proteins unrelated to the classical nuclear receptors have been proposed to play ... more Steroid-binding proteins unrelated to the classical nuclear receptors have been proposed to play a role in non-genomic effects of steroid hormones. We have previously described that the low-affinity glucocorticoid binding protein (LAGS), present in the endoplasmic reticulum of the male rat liver, has pharmacological and biochemical properties different from those of nuclear receptors. The LAGS is under multihormonal regulation and binds glucocorticoids, progestins, and synthetic steroids but is unable to bind either estradiol, testosterone, or triamcinolone acetonide. In this study, we have solubilized the LAGS and investigated their pharmacological and hydrodynamic properties and their peptide composition. We found that LAGS is an integral protein bound to the endoplasmic reticulum. CHAPS provided its optimal solubilization without changes in its pharmacological properties. Hydrodynamic properties of LAGS showed that it has a molecular mass of at least 135 kDa. SDS-PAGE of covalently-labeled LAGS showed that [ 3 H]dexamethasone binds two peptides of 53 and 37 kDa, respectively. Thus, the LAGS appears as an oligomeric protein under multihormonal regulation. The availability of solubilized LAGS and the fact that it can be induced in vivo represent major steps toward purification and understanding the functional significance of this unique steroid-binding protein.
Urologic Oncology-seminars and Original Investigations
Objective: The present study was aimed at examining the local distribution of GSTM1, GSTT1, MDR1,... more Objective: The present study was aimed at examining the local distribution of GSTM1, GSTT1, MDR1, and VEGF gene polymorphisms as possible risk factors contributing to the development of bladder cancer among the population from Canary Islands, Spain.
Environmental Toxicology and Pharmacology, 2007
Our multigenerational study evaluates the hepatic effects of the xenoestrogens nonylphenol (NP), ... more Our multigenerational study evaluates the hepatic effects of the xenoestrogens nonylphenol (NP), and 4-octylphenol (4OP) on male and female rats when they are exposed uninterruptedly, from conception to adult age, to tap water containing 25 ppm of NP or 4OP. Our results showed that these compounds did not induce any change in liver/body weight ratio (relative liver weight, RLW). In the morphological analysis we did not find evident signs of cytotoxicity. The most relevant findings were the presence of both an increase in the apoptotic index and in the percentage of binuclear hepatocytes in livers from exposed animals. Additionally, our study revealed the presence of hepatocellular glycogenosis (mainly in 4OP-exposed rats): the type of glycogen accumulated was in aggregates (gamma-glycogen), a non-functional form of glycogen. This study demonstrates that, at levels close to those described in the environment, NP and 4OP are capable of inducing a number of hepatic effects, potentially related with adaptive, and/or metabolic alterations of liver tissue.
Growth Hormone & Igf Research, 2010
Context: Serum levels of Insulin-like growth factor I (IGF-I) play a critical role in children gr... more Context: Serum levels of Insulin-like growth factor I (IGF-I) play a critical role in children growth and in the pathogenesis of several diseases. In addition, recent studies suggest that DDT-derivative organochlorine pesticides (OC-DDTs) could influence IGF levels in human beings. Objective and design: Because it has been suggested that IGF-I peak levels at puberty could determine IGF-I levels in adulthood, we developed a cross-sectional study of the potential association between serum levels of OC-DDTs and IGF system in 160 serum samples from young people (81 boys and 79 girls) living in the Canary Islands (Spain). Results: Multivariate tests were used adjusting for confounding variables (age, height, and weight) and stratifying by gender and age: IGF-I serum levels were significantly lower in pre-pubertal male children (6-15 years) who showed detectable values of p,p 0 -DDE, and p,p 0 -DDD than in pre-pubertal male children with undetectable levels of these OC-DDTs-metabolites (p = 0.023 and p = 0.049, respectively). In addition, in this multivariate model, a non-linear dose-response curve was observed between Total DDT body burden (sum of the three DDT-derivatives measured: p,p 0 -DDT, p,p 0 -DDE, and p,p 0 -DDD) and IGF-I in prepubertal male children (6-15 years; p = 0.043). Conclusion: These findings suggest that OC-DDTs could modulate the IGF-system in a way that is highly influenced by gender and age. Improvements in our understanding of exogenous determinants of the IGFsystem may provide new insights into the role played by environmental contaminants in IGF-related diseases.
Journal of Steroid Biochemistry and Molecular Biology, 2002
Prostate carcinoma is the most frequently diagnosed malignancy and the second leading cause of de... more Prostate carcinoma is the most frequently diagnosed malignancy and the second leading cause of death as a result of cancer in men in the western countries. Withdrawal of androgens or the peripheral blockage of androgen action remain the critical therapeutic options for the treatment of advanced prostate cancer. However, after initial regression, most of the prostate cancers become androgen-independent and progress further, with eventual fatal outcome. Understanding the mechanisms of transition to androgen independence and tumor progression in prostate cancer is critical to finding new ways to treat aged patients that are ineligible for conventional chemotherapy. A large number of different molecular mechanisms might be responsible for the transition to androgen-independence. Many of these involve the androgen receptor (AR) and its signalling pathways, but they might also include genetic changes that affect several genes, which results in the activation of oncogenes or the inactivation of tumor suppressor genes. Here, we discuss the most recent and relevant findings on androgen resistance in prostate cancer in order provide a comprehensive interpretation of the clinical behaviour of tumors at molecular levels.
Science of The Total Environment, 2006
Organochlorine pesticides are a lipophilic class of chemicals that persist in the environment and... more Organochlorine pesticides are a lipophilic class of chemicals that persist in the environment and tend to accumulate in human tissues for years. They came into widespread use in the late 1940s. Because of their capacity to bioaccumulate and biomagnify in food chains and their toxic effects, most of them were banned in industrialized countries, among them Spain, in the late 1970s and 1980s. In 1998 organochlorine pesticides were determined in a representative sample of a Spanish population (around 690 serum samples from people 6 to 75years old from the Canary Islands). Serum levels of lindane aldrin, dieldrin and endrin, were determined. Our results showed that a high percentage of samples presented detectable levels of some of the organochlorines measured, endrin being the most frequently detected (72%) and at highest concentration (mean 136.7ng/g fat). Mean concentrations of the main cyclodiene evaluated, dieldrin, was lower to those found in other Western populations. However, serum levels of lindane were higher than those described in North European populations. Influence of geographical and sociodemographic factors was evaluated. Urban populations showed the highest levels of dieldrin, while non-urban population showed the highest serum values of lindane, aldrin and endrin. Unexpectedly, serum values of lindane, aldrin and dieldrin were higher in younger than in older people. Subjects under 18years showed almost twice as high serum levels of lindane, aldrin and dieldrin than subjects of 65-75years. These results may well suggest that people living in the Canary Islands have been and are currently exposed to non-DDT-organochlorine pesticides. The type and source of exposure could vary between islands and type of habitat. Contaminated food and/or the environment could be related with this situation.
Growth Hormone & Igf Research, 2007
Context: Insulin-like growth factor 1 (IGF-I) and organochlorine pesticides (OCs) have been invol... more Context: Insulin-like growth factor 1 (IGF-I) and organochlorine pesticides (OCs) have been involved in the pathogenesis of several diseases like cancer, diabetes and growth disorders. Objective and design: The potential relationship between the serum levels of various OCs and serum IGF-I was investigated in adults (176 men and 247 women) from a representative sample of the general population of the Canary Islands (Spain). Results: After adjustment for potential confounders, which include body mass index, age, and IGF-binding protein-3 (IGFBP-3), IGF-I levels were significantly lower in the 247 women who showed detectable levels of p,p 0 -DDD (a DDT-metabolite) than in women who presented non-detectable levels of this pesticide (p = 0.030), specially in 36-50 years old women. A similar negative relationship was also found between IGF-I and aldrin (a non-DDT-derivative) in women (p = 0.049). In the group of 176 men, aldrin seemed to exert a similar negative effect on IGF-I (p = 0.046) and this effect was clearly significant in the oldest group (51-65 years) (p = 0.009). A non-linear dose-response curve was observed between Total Cyclodienes Body Burden (Total Cyclodienes; sum of aldrin, dieldrin and endrin) and IGF-I in men (p = 0.024). These findings suggest that OCs could modulate the IGF-system in a way that is highly influenced by gender, age and by chemical or combination of chemicals implicated. Such circumstances may contribute to the development of a number of diseases related to IGF-I and should be taken into account in public health decisions.
Archives of Toxicology, 1999
Stanozolol (ST) is a 17α-alkyl anabolic-androgenic steroid (17α-AAS) often misused by athletes an... more Stanozolol (ST) is a 17α-alkyl anabolic-androgenic steroid (17α-AAS) often misused by athletes and bodybuilders. The use of anabolic-steroids by sportsmen and teenagers has increased dramatically, thus raising the question about their hepatotoxicity, specially those such as ST which are orally administered. Previously, we have reported diverse in vivo effects exerted by this steroid and published the existence of a highly specific ST-binding site in male rat liver microsomes. The existence of this binding site, the reported hepatic effects exerted in humans, and the very limited information about its potential hepatotoxicity led us to treat adult male rats acutely and chronically with ST and study different parameters that could indicate liver damage: serum levels of transaminases, concentration of monooxygenase enzymes in liver, liver membrane lipid peroxidation products, liver histopathology, and cell cycle/ploidy status of liver cells. In our study, no changes in serum transaminases or lipid peroxidation levels were obtained. However, acute stanozolol treatment significantly decreased the levels of cytochrome P450 (Cyt. P450) and cytochrome b5 (Cyt. b5) during the first 48 h of treatment, while subsequently, at 72 and 96 h, these microsomal enzymes underwent a significant increase in their levels. In sharp contrast with this response to acute treatment, the content of these two enzymes during chronic treatment showed an important decrease. Interestingly, acutely and chronically ST-treated livers showed slight to moderate inflammatory or degenerative lesions in centrilobular hepatocytes. Flow cytometric analysis demonstrated that both acute and chronic ST treatment were capable of increasing the percentage of S-phase fraction (%SPF) of liver cells. These findings taken together clearly show that this steroid is capable of altering the liver capacity for metabolizing xenobiotics and indicate that high doses of ST could exert a proliferative effect on liver cells. Such data should be considered in risk evaluations for this compound.
Endocrinology, 2000
We have demonstrated previously that both rat and human liver microsomes contain a highly specifi... more We have demonstrated previously that both rat and human liver microsomes contain a highly specific binding protein for the anabolic steroids stanozolol (ST) and danazol (DA). In this study we solubilized the male rat liver ST-binding protein (STBP) and investigated the following parameters: 1) pharmacological properties, 2) hydrodynamic properties, 3) peptidic composition, 4) the effects of age and hypophysectomy, and 5) inducibility by 17␣-ethinyl estradiol. We found that STBP is an integral protein bound to the endoplasmic reticulum. 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS) provided its optimal solubilization without changes in its pharmacological properties, i.e. high specificity for ST and danazol, between natural steroids and ligands of low affinity glucocorticoid-binding sites or of progesterone-binding sites. Hydrodynamic properties of the STBP showed that it has a molecular mass of at least 118 kDa. SDS-PAGE of covalently labeled STBP under nonreducing conditions showed that [ 3 H]ST binds to a 110-kDa protein. The STBP was resolved under reducing conditions into three peptides of 55, 31, and 22 kDa, respectively. STBP increased from immature to adult rats, and it dramatically decreased after hypophysectomy. Unlike the 22-kDa peptide, both the 55-and 31-kDa peptides drastically decreased in both immature and hypophysectomized rats. 17␣-Ethinyl estradiol administration to immature or hypophysectomized rats induced the 55-and 31-kDa [ 3 H]STBP to a greater extent than the 22-kDa peptide. Thus, STBP appears as an oligomeric protein composed of hormone-regulated peptides. The availability of solubilized STBP and the fact that it can be induced in vivo represent major steps toward the purification and functional significance of this unique steroid-binding protein.
Environmental Research, 2009
Organochlorines (OCs) tend to accumulate in human tissues and can be measured in amniotic fluid (... more Organochlorines (OCs) tend to accumulate in human tissues and can be measured in amniotic fluid (AF). The detection of OCs in AF samples reflects intrauterine exposure of human beings to these persistent organic pollutants. The present study was performed to evaluate the level of contamination of AF by OCs in 100 pregnant women from Tenerife Island (Canary Islands, Spain). Gas chromatography/mass spectrometry (GC/MS) was used to identify and quantify the analytes, including 7 polychlorobiphenyl (PCB) congeners and 18 OC pesticides and metabolites. The majority of the AF samples (67%) showed some detectable OC-residue, hexachlorobenzene (HCB) being the most frequently detected compound (66% of the samples) and at the highest concentration (median 0.023 ng/ml). Lindane was also detected in 28% of the samples. Inverse associations were found between previous lactation and hexachlorocyclohexane isomers (HCH) and cyclodienes in the group of younger women (p ¼ 0.037 and p ¼ 0.027, respectively). Unexpectedly, serum values of HCB (r ¼ À0.414; p ¼ 0.04), g-HCH (r ¼ À0.294; p ¼ 0.035), and P OCs (r ¼ À0.350; p ¼ 0.014) were negatively related to age. Even more, women with detectable levels of HCH isomers were younger (33.974.9 years) than women with undetectable levels of them (36.174.9 years; p ¼ 0.035). We conclude that approximately one in two fetuses in the Canary Islands is exposed to OCs in utero, and that, therefore, the exposure of young women from these Islands to some HCH isomers persists nowadays. Because prenatal exposure to these chemicals may be a causative factor in adverse health trends, further studies are required to enhance preventive measures.
Urologic Oncology-seminars and Original Investigations
Objective: The present study was aimed at examining the local distribution of GSTM1, GSTT1, MDR1,... more Objective: The present study was aimed at examining the local distribution of GSTM1, GSTT1, MDR1, and VEGF gene polymorphisms as possible risk factors contributing to the development of bladder cancer among the population from Canary Islands, Spain.
Toxicology Letters, 2010
Fumonisins (FB) are mycotoxins produced by Fusarium verticillioides, frequently associated with c... more Fumonisins (FB) are mycotoxins produced by Fusarium verticillioides, frequently associated with corn. It produces speciesspecific and organ-specific toxicity, including teratogenicity, equine leukoencephalomalacia, porcine pulmonary edema, and hepatic or renal damage in most animal species. FB interferes with ceramide synthase leading to intracellular accumulation of sphingoid bases which mediate several key biological processes such as cell proliferation, and DNA replication, inhibits biosynthesis of cellular macromolecules and induces lipid peroxidation in rat hepatocytes. The current study was conducted to evaluate the protective effect of the ethanol extract of jojoba in rats fed FB-contaminated diet. Forty mature male Sprague-Dawley were divided into four treatment groups and treated for 3 weeks as follow: the control group, the group fed FB-contaminated diet (150 mg/kg), the group treated orally with jojoba extract (5 mg/kg b.w.) and the group fed FB-contaminated diet and treated with the extract. At the end of treatment period, blood and liver samples were collected for heamatological, biochemical and histological studies. The results indicated that FB induced significant decrease in red blood cells count, hemoglobin concentration, platelets, white blood cells count, cholesterol and total antioxidant capacity (TAC) and a significant increase in ALT, AST, ALP, LDH, CK, urea, createnine, uric acid and lipid peroxidation (MDA) accompanied with severe pathological changes in the liver tissues. Animals treated with jojoba extract alone were comparable to the controls regarding the heamatological and the biochemical parameters and the histological picture of the liver. The extract contracted the toxic effects of FB and succeeded to normalize all the parameters tested and the histological picture of the liver.
Environmental Toxicology and Pharmacology, 2007
Our multigenerational study evaluates the hepatic effects of the xenoestrogens nonylphenol (NP), ... more Our multigenerational study evaluates the hepatic effects of the xenoestrogens nonylphenol (NP), and 4-octylphenol (4OP) on male and female rats when they are exposed uninterruptedly, from conception to adult age, to tap water containing 25 ppm of NP or 4OP. Our results showed that these compounds did not induce any change in liver/body weight ratio (relative liver weight, RLW). In the morphological analysis we did not find evident signs of cytotoxicity. The most relevant findings were the presence of both an increase in the apoptotic index and in the percentage of binuclear hepatocytes in livers from exposed animals. Additionally, our study revealed the presence of hepatocellular glycogenosis (mainly in 4OP-exposed rats): the type of glycogen accumulated was in aggregates (gamma-glycogen), a non-functional form of glycogen. This study demonstrates that, at levels close to those described in the environment, NP and 4OP are capable of inducing a number of hepatic effects, potentially related with adaptive, and/or metabolic alterations of liver tissue.
Environmental Research, 2011
Polychlorinated biphenyls (PCBs) are persistent and toxic compounds that have been detected in hu... more Polychlorinated biphenyls (PCBs) are persistent and toxic compounds that have been detected in human serum or tissues worldwide. The objective of our study was to determine serum PCB levels in a representative sample of the general population of the Spanish Archipelago of the Canary Islands (607 serum samples from subjects aged between 6 and 75 years) in order to establish the main causes of this contamination and to evaluate the potential risks posed by these chemicals on the population through the use of toxicity equivalence to dioxins (TEQs). PCB congeners (28, 52, 77, 81, 101, 105, 114, 118, 123, 126, 138, 153, 156, 157, 167, 169, 180, and 189) were measured by gas chromatography-mass spectrometry (GC/MS). Our results showed that PCB residues were found in 76% of serum samples analyzed, with the congeners 153 and 180 being the most frequently detected and having the highest median values (21.8 and 6.7 ng/g lipid, respectively). Serum levels of non-dioxin-like PCBs increased with age, body mass index (BMI), urban habitat, and smoking. The median concentration of the sum of PCBs considered as markers of environmental contamination by these chemicals (M-PCBs) was 46.4 ng/g lipid. Levels of the sum of dioxin-like PCBs (DL-PCBs) were 48.5 ng/g lipid in the 95th percentile, and were also positively associated with age. As a consequence, age seemed to be positively associated with TEQs levels, reaching values as high as 58.6 pg/g lipid in the serum samples from oldest people. Our results indicate that the inhabitants of the Canary Archipelago show levels of PCB contamination lower than other populations present on the Spanish mainland, as well as many populations from developed countries. Nevertheless, as these compounds may induce adverse health effects even at very low doses, our findings should be considered by local Public Health authorities in order to establish measures for diminishing the exposure of the population of these islands to PCBs.
Toxicology Letters, 2010
Abstracts / Toxicology Letters 196S (2010) S37-S351 tion procedure was in HR-P columns preconditi... more Abstracts / Toxicology Letters 196S (2010) S37-S351 tion procedure was in HR-P columns precondition with methanol and water. The subsequent elution of diazinon was performed with a mixture of hexane-ethyl acetate (1:1, v/v) prior to the determination by GC-NPD and GC-MS/MS. Standards were prepared spiking blank juice samples to contract the observed matrix effect. Accuracy (<9/6%), precision (<7/1%), specificity (quantitative, no peaking interaction), sensitivity LOD(1) ng/ml and LOQ(5) ng/ml and reproducibility (>95/4%) were acceptable. Detection limit was 1 ng/ml. Linear relation with good correlation coefficients (R 2 > 0/99) was obtained. Mean recovery for diazinon was 95/4% with relative standard deviation lower than 9% in the concentration range of 5-200 ng/ml. Mean and SD of diazinon in melons was 107/64 ± 38/5 ng/kg. Diazinon was not detected in cucumber samples. It was later confirmed that diazinon was not used for the crops of these cucumbers. GC-NPD and MS/MS was developed to determine residue of diazinon in melons and cucumbers. The GC-MS/MS analytical method showed a high efficacy for determination of diazinon residues in the fruits Insulin-like growth factor 1 (IGF-I) and its binding proteins (mainly, IGFBP-3) and DDT-derivative pesticides (DDTs) have been involved in the pathogenesis of several malignancies, such as cancer, diabetes and growth disorders. Recently, it has been suggested that DDTs may influence IGF levels in adults. Due to the fact that IGF-I peak levels at puberty could determine IGF-I levels in adulthood, we developed a cross-sectional study to evaluate the potential relationship between the serum levels of DDTs and IGF-I in youngsters (160 people between 6 and 19 years; 81 boys and 79 girls) from a representative sample of the general population of the Canary Islands (Spain). Multivariate models (ANCOVA) tests were used adjusting for confounding variables (age, BMI, and IGFBP-3), and stratifying by gender. Our results showed that IGF-I serum levels were significantly lower in pre-pubertal male children (6-15 years) who showed detectable levels of p,pǐ-DDE and p,pǐ-DDD than in pre-pubertal male children who presented non-detectable levels of these DDTs (p = 0.023 and p = 0.049, respectively). Additionally, in this multivariate model, a non-linear dose-response curve was observed between Total DDT body burden (sum of the three DDTs measured in serum: p,pǐ-DDT, p,pǐ-DDE, and p,pǐ-DDD) and IGF-I in pre-pubertal male children (p = 0.043). These findings agree with previous studies that related p,pǐ-DDE serum levels with decreased height and weight in children. Our results seem to indicate that DDTs could modulate the IGF-system in a way that is highly influenced by gender and age. Such circumstance implies that environmental contaminants could influence the long-term risk of several diseases related to GH-IGF axis (diabetes, cancer, allergies, growth disorders, etc.).
Los plaguicidas organoclorados (OCs) son contaminantes universalmente extendidos, detectables en ... more Los plaguicidas organoclorados (OCs) son contaminantes universalmente extendidos, detectables en casi todos los sistemas biológicos debido a su alta estabilidad y liposolubilidad. Este estudio determina la presencia del DDT (p,p´-DDT) y su principal metabolito el DDE (p,p´-DDE) en una muestra representativa de la población del Archipiélago Canario. En éste se ha impuesto en las últimas décadas la agricultura intensiva, utilizando grandes cantidades de pesticidas, entre ellos el DDT (prohibido en España y Europa al final de la década de los 70). Dado que los OCs presentan una alta persistencia en el ambiente y sufren biomagnificación y bioamplificación en la cadena trófica, el estudio cuantitativo de la presencia residuos de estos compuestos en suero humano nos indica la exposición pasada y presente a los mismos. Nuestros resultados demuestran que el conjunto de la población canaria, presenta unos niveles muy superiores a la media europea y que sigue existiendo una exposición a este producto en nuestros días. Resumiendo, según nuestro estudio, el perfil tipo de la persona expuesta a mayores niveles de estos contaminantes en las Islas Canarias es: mujer, mayor de 20 años, residente en Gran Canaria en un área semiurbana o urbana.
Toxicology Letters, 1996
Poster Session 1E. Mechanism of Toxicity immunostaining showed a significant increase in nucleus ... more Poster Session 1E. Mechanism of Toxicity immunostaining showed a significant increase in nucleus ambiguous, nucleus tractus solitarius and lateral reticular nucleus after acute exposure in vivo to this solvent in rats.
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Papers by Octavio Pérez Luzardo