RESUMEN
BACKGROUND: Diabetes mellitus (DM) and deficiency in n-3 long-chain polyunsaturated fatty acids (n-3 LCPUFAs) are known to increase the incidence of cardiovascular disease (CVD). However, it has not yet been reported whether n-3 LCPUFAs are related to arteriosclerosis in patients under long-term hemodialysis (HD). METHODS: Pulse wave velocity from the brachium to the ankle (baPWV) was measured as a marker of arteriosclerosis with a volume-plethysmographic apparatus in 147 long-term HD patients (non-diabetic (non-DM): 51 males/42 females, 62 +/- 14 y; and DM: 33 males/21 females, 67 +/- 9 y). The fatty acid composition of the total phospholipid fraction from washed RBCs was analyzed by gas chromatography. Analyses were adjusted for age, sex, diastolic blood pressure, pulse, body mass index, duration of HD treatment, smoking status, LDL/HDL-cholesterol ratios and diabetes mellitus (DM). RESULTS: The mean baPWV was 18.9 +/- 5.2 and 23.7 +/- 6.3 m/s in non-DM and DM patients, respectively. The mean baPWV in DM patients was significantly higher than that of non-DM patients after adjustment (p = 0.0002). Multiple regression analysis showed that there was a significant inverse association between baPWV and docosahexaenoic acid (DHA) levels (p = 0.017) and DHA/arachidonic acid (AA) ratios (p = 0.012) in RBC in non-DM patients after adjustment but not in DM patients. CONCLUSIONS: We suggest that n-3 LCPUFAs may be a negative risk factor of CVD also in non-DM HD patients. In DM patients the effects of n-3 PUFAs on the vascular system became undetectable probably because DM overwhelmingly affected PWV. Further studies in a prospective manner are necessary.
Asunto(s)
Aterosclerosis/fisiopatología , Arteria Braquial/fisiología , Diabetes Mellitus/sangre , Ácidos Grasos Omega-3/sangre , Flujo Pulsátil/fisiología , Diálisis Renal/métodos , Anciano , Aterosclerosis/sangre , Aterosclerosis/epidemiología , Colesterol/sangre , Cromatografía de Gases , Cromatografía en Capa Delgada , Diabetes Mellitus/terapia , Femenino , Estudios de Seguimiento , Humanos , Incidencia , Japón/epidemiología , Fallo Renal Crónico/sangre , Fallo Renal Crónico/fisiopatología , Fallo Renal Crónico/terapia , Masculino , Persona de Mediana Edad , Pletismografía , Pronóstico , Factores de Riesgo , Factores de TiempoRESUMEN
41 students took either docosahexaenoic acid (DHA)-rich oil capsules containing 1.5-1.8 grams DHA/day (17 females and 5 males) or control oil capsules containing 97% soybean oil plus 3% fish oil (12 females and 7 males) for 3 mo in a double-blind fashion. They took a psychological test (P-F Study) and Stroop and dementia-detecting tests at the start and end of the study. The present study started at the end of summer vacation and ended in the middle of mental stress such as final exams. In the control group extraggression (aggression against others) in P-F Study was significantly increased at the end of the study as compared with that measured at the start (delta = +8.9%, P = 0.0022), whereas it was not significantly changed in the DHA group (delta = -1.0%). The 95% CI of differences between the DHA and control groups were -16.8 to -3.0%. DHA supplementation did not affect the Stroop and dementia-detecting tests. Thus, DHA intake prevented extraggression from increasing at times of mental stress. This finding might help understand how fish oils prevent disease like coronary heart disease.
Asunto(s)
Agresión/fisiología , Ácidos Docosahexaenoicos/farmacología , Adulto , Demencia/fisiopatología , Grasas de la Dieta/metabolismo , Método Doble Ciego , Ácidos Grasos no Esterificados/metabolismo , Femenino , Humanos , MasculinoRESUMEN
Pulse wave velocity (PWV) of the aorta was measured in 55 inhabitants of fishing villages and in 49 inhabitants of farming villages, where people normally eat less fish than in the fishing villages. The PWV was significantly slower (indicating less sclerosis) in the fishing villages than in the farming villages (P less than 0.005). This is consistent with a lower incidence of ischemic heart disease in a coastal area, which includes the fishing villages, than in a mountainous area, including the farming villages. It is reported that a long-term fish-diet slows down sclerotic changes of arteries.
Asunto(s)
Aorta/fisiología , Arteriosclerosis/epidemiología , Dieta , Peces , Pulso Arterial , Adulto , Animales , Aorta/fisiopatología , Enfermedades de la Aorta/epidemiología , Enfermedades de la Aorta/fisiopatología , Arteriosclerosis/diagnóstico , Arteriosclerosis/fisiopatología , Velocidad del Flujo Sanguíneo , Trastornos Cerebrovasculares/mortalidad , Enfermedad Coronaria/mortalidad , Femenino , Humanos , Japón , Masculino , Persona de Mediana Edad , Población RuralRESUMEN
Fish oil concentrate (5.4 g/day) was administered to 8 young male volunteers and to 7 middle-aged male volunteers for 1 week. ADP released into the supernatant of red blood cell (RBC) suspension by a shear stress of 375/sec for 3 min was measured before and after fish oil administration. Before the administration the ADP release from shear-stressed RBCs in the middle-aged group was significantly higher than in the young group. After the administration the ADP release was reduced significantly in the young group (by 46%, p less than 0.001) and nonsignificantly in the middle-aged group (by 54%, p = 0.09). If the two groups were combined, the reduction was also significant (by 50%, p less than 0.005). This reduction was significantly correlated with the improvement of RBC filterability after fish oil administration (n = 13, r = 0.62, p less than 0.05). We suggest that the reduction of the ADP release from shear-stressed RBCs is one of the mechanisms of action of eicosapentaenoic acid against thrombotic disease.
Asunto(s)
Adenosina Difosfato/metabolismo , Eritrocitos/efectos de los fármacos , Aceites de Pescado/farmacología , Adulto , Factores de Edad , Viscosidad Sanguínea/efectos de los fármacos , Deformación Eritrocítica/efectos de los fármacos , Membrana Eritrocítica/química , Eritrocitos/metabolismo , Humanos , Masculino , Lípidos de la Membrana/análisis , Persona de Mediana Edad , Trombosis/prevención & controlRESUMEN
Cilostazol is an anti-thrombotic and vasodilating agent, reported to have both anti-thrombotic and cerebral vasodilating effects. We investigated the effects of cilostazol on serum lipid concentrations and plasma fatty acid composition in type 2 diabetic patients with peripheral vascular disease. The serum concentrations of total cholesterol, triglycerides, high-density lipoprotein-cholesterol, lipoprotein (a), remnant-like particles-cholesterol, apolipoproteins, and plasma fatty acid composition were measured in 17 diabetic patients with peripheral vascular disease before and 1, 3, and 6 months after administration of cilostazol (200 mg/day). Serum triglyceride concentrations were significantly decreased after cilostazol (from 1.31+/-0.17 mmol/l to 0.86+/-0.07 mmol/l at 6 months, P<0.01). Plasma docosahexaenoic acid levels were significantly increased after cilostazol (4.11+/-0.26% to 4.94+/-0.26% at 6 months, P<0.01). Our findings show that cilostazol can induce some beneficial changes in serum lipid profile and plasma fatty acid composition.
Asunto(s)
Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/patología , Ácidos Grasos/sangre , Lípidos/sangre , Enfermedades Vasculares Periféricas/metabolismo , Tetrazoles/metabolismo , Vasodilatadores/metabolismo , Anciano , Apolipoproteínas/sangre , Arteriosclerosis/tratamiento farmacológico , Arteriosclerosis/metabolismo , Glucemia/metabolismo , Cilostazol , Ayuno , Femenino , Hemoglobina Glucada/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Estructura Molecular , Tetrazoles/química , Tetrazoles/uso terapéutico , Vasodilatadores/química , Vasodilatadores/uso terapéuticoRESUMEN
We previously found that docosahexaenoic acid (DHA) intake prevents aggression enhancement at times of mental stress. In the present study we investigated changes in aggression under nonstressful conditions. Forty-six students of two universities took either DHA-rich fish oil capsules containing 1.5 g DHA (DHA group: 13 males and 9 females) or control oil capsules containing 97% soybean oil plus 3% of another fish oil (control group: 11 males and 13 females) for 3 mon in a double-blind fashion. At the start and end of the study they took an aggression-estimating test (P-F Study) without a stressor component. DHA (5.9 to 8.5%, P < 0.001) and eicosapentaenoic acid (0.7 to 1.5%, P < 0.001) increased in red blood cell phospholipids in the DHA group, while linoleic acid increased slightly (8.3 to 9.1%, P < 0.002) in the soybean oil control group. In the control group, measured aggression levels decreased from 34.8 to 29.4% (P < 0.005), whereas they remained stable in the DHA group (33.5 to 33.8%). The intergroup differences (-5.4 vs. 0.3%) were marginally significant (P < or = 0.05). Aggression levels were stable in the DHA group whether there was stressor (as previously shown) or not. This effect of DHA appears to be interesting, considering the reported association between a low intake of n-3 fatty acids and depression.
Asunto(s)
Agresión/efectos de los fármacos , Grasas de la Dieta/uso terapéutico , Ácidos Docosahexaenoicos/uso terapéutico , Aceites de Pescado/uso terapéutico , Estrés Fisiológico/tratamiento farmacológico , Adulto , Método Doble Ciego , Eritrocitos/efectos de los fármacos , Eritrocitos/metabolismo , Femenino , Humanos , Masculino , Fosfolípidos/sangreRESUMEN
The purpose of the present research was to clarify the effect of docosahexaenoic acid (DHA) intake on behavior and plasma catecholamines (CA). In Study 1, 42 students took either DHA-rich oil capsules containing 1.5-1.8 g DHA/d or control oil capsules containing 97% soybean oil plus 3% of another fish oil for 3 mon in a double-blind fashion. They took a psychological test (PF Study) at the start and end of the study. This study started at the end of summer vacation and ended just before the final exams. In the control group, external aggression (aggression against others) in PF Study was significantly increased at the end of the study as compared with that measured at the start (+8.9%), whereas it was not significantly changed in the DHA group (-1.0%). In a similar double-blind study (Study 2), we measured external aggression under nonstressful conditions. External aggression slightly decreased in the control group, whereas there were no significant changes in the DHA group. In Study 3 with 14 students, plasma CA were measured at the start and end of capsule administration period of 2 mon. Subjects were under continuous stress of the final exams that lasted throughout the whole study period. The ratio of plasma epinephrine to norepinephrine concentrations was significantly increased in the DHA group (78%), whereas it stayed at the same level in the control group. In Study 4, mice were fed either DHA-deficient diet or -sufficient diet for 4 wk, and their rearing frequency (an anxiety index) was measured. In the DHA-sufficient group, the rearing frequency was significantly less than in the other group. These effects of DHA intake may be applied to people in an attempt to ameliorate stress-related diseases.
Asunto(s)
Catecolaminas/sangre , Ácidos Docosahexaenoicos/farmacología , Estrés Psicológico/sangre , Adulto , Agresión/efectos de los fármacos , Animales , Método Doble Ciego , Humanos , Ratones , Actividad Motora/efectos de los fármacos , Placebos , Pruebas Psicológicas , Encuestas y CuestionariosRESUMEN
Streptozotocin (45 mg/kg) was intravenously administered to 7-week-old Wistar rats through their tail veins. After 11 days, the rats were divided into two groups. One group was fed a lipid-free diet (90%, w/w) plus lard (8%) and safflower oil (2%) for four weeks (Diet 1 group, n = 12). The other group was fed in the same way, except that safflower oil was replaced by 90% pure eicosapentaenoic acid (EPA) ethyl ester (Diet 2 group, n = 13). Twenty-four-hour urine was collected just before the diets started and during the experiment at 7-day intervals. In the second and third week, the levels of proteinuria were significantly lower in the Diet 2 group than they were in the Diet 1 group. There was no significant difference in the levels of creatinine, urea nitrogen, or lipids in plasma or in body weights between the two groups after four weeks on the diets. Because Diet 2 reduced proteinuria of diabetic rats compared to Diet 1, an EPA-rich diet may retard the development of diabetic nephropathy.
Asunto(s)
Diabetes Mellitus Experimental/metabolismo , Proteinuria/metabolismo , Animales , Glucemia , Peso Corporal , Grasas de la Dieta/análisis , Ácido Eicosapentaenoico/administración & dosificación , Ácido Eicosapentaenoico/farmacología , Ácidos Grasos/análisis , Glucosuria , Riñón/metabolismo , Lípidos/sangre , Masculino , Ratas , Ratas Endogámicas , EstreptozocinaRESUMEN
DHA is abundant in the brain. Deficiency of DHA changes behavior in animals. The purpose of the present studies was to clarify the effect of DHA intake on hostility and plasma catecholamines. In study 1, forty-one students took either DHA-rich oil capsules containing 1.5-1.8 g DHA/d (17 females and 5 males) or control oil capsules containing 97% soybean oil plus 3% fish oil (12 females and 7 males) for 3 mon in a double blind fashion. They took a psychological test (P-F Study) at the start and end of the study. Study I started at the end of summer vacation and ended in the middle of mental stress of final exams. In the control group, hostility measured by P-F Study was significantly increased at the end of the study as compared with that measured at the start (+58%), whereas it was not significantly changed in the DHA group (-14%). In a similar double blind two-mon study (study 2), we measured plasma catecholamines and cortisol of students (3 females and 4 males for the DHA group and the same numbers for the control) at the start and end of the study. In study 2 the students were under a continuous stress of final exams that lasted for two mon throughout the whole study period. The plasma cortisol did not change in either group, but the norepinephrine concentration was significantly decreased in the DHA group (-31%), whereas it stayed at the same level in the control group. These effects of DHA intake may be applied to people under psychological stress.
Asunto(s)
Ácidos Docosahexaenoicos/farmacología , Epinefrina/sangre , Hostilidad , Norepinefrina/sangre , Estrés Psicológico/prevención & control , Adulto , Animales , Método Doble Ciego , Femenino , Humanos , Masculino , Pruebas PsicológicasRESUMEN
We previously found that docosahexaenoic acid (DHA) intake prevented aggression from increasing at times of mental stress. In the present study, we investigated whether DHA intake modified the plasma catecholamines and cortisol of medical students during a 9-wk period of final exams. We also investigated the effects of DHA intake on a 75 g oral glucose tolerance test (oGTT). Fourteen medical students participated in the present study. They were randomly allocated to either control or DHA group in a double-blind manner. Subjects in the control group (4 males and 3 females) took 10 control capsules/d, each capsule containing 280 mg of mixed plant oil, and those in the DHA group (4 males and 3 females) took 10 DHA capsules/d containing 1.5 g DHA for 9 wk, during which subjects underwent more than 20 stressful final exams. At the start and end of the study, plasma catecholamines (epinephrine, norepinephrine (NE) and dopamine) and cortisol were measured; a 75 g oGTT was also performed. There were no intra- or intergroup differences in plasma glucose concentrations. However, NE concentrations were significantly reduced after DHA administration (-31%, p < 0.03). The other catecholamines and cortisol did not change significantly. The plasma ratio of epinephrine to NE increased in every DHA subject (+78%, p < 0.02), and intergroup differences were significant (p < 0.03). We conclude that these effects of DHA may be applied to people under long-lasting psychological stress to prevent stress-related diseases.
Asunto(s)
Ácidos Docosahexaenoicos/farmacología , Dopamina/sangre , Epinefrina/sangre , Prueba de Tolerancia a la Glucosa , Norepinefrina/sangre , Estrés Psicológico/sangre , Adulto , Glucemia/metabolismo , Grasas de la Dieta/administración & dosificación , Método Doble Ciego , Eritrocitos/química , Ácidos Grasos/sangre , Femenino , Humanos , Insulina/sangre , Masculino , PlacebosRESUMEN
The effect of age on eicosapentaenoic acid (20:5 n-3; EPA) incorporation into plasma lipids was investigated in young volunteers (8 males, 19 +/- 1 yr) and middle-aged volunteers (6 males, 53 +/- 7 yr). They were asked to take 5.4 g fish oil per day for one week. The increment in EPA in the cholesteryl ester fraction after the supplementation was significantly greater in the middle-aged group (delta = 1.69%) than in the young group (delta = 0.44%) (p less than 0.05). The food intake analyzed for 3 consecutive days just before the supplementation revealed that the young group took more linoleate (17 vs. 10 g) than the middle-aged group. There was a significant inverse correlation between the increment in EPA in the cholesteryl ester fraction after the supplementation and daily linoleate intake among all the volunteers combined (r = -0.63, p less than 0.02). The higher increment in EPA in cholesteryl ester in the middle-aged group might be due to less intake of linoleate and not due to the difference in age itself.
Asunto(s)
Envejecimiento/sangre , Ácido Eicosapentaenoico/sangre , Aceites de Pescado/metabolismo , Administración Oral , Adulto , Ácidos Grasos/sangre , Aceites de Pescado/administración & dosificación , Humanos , Ácido Linoleico , Ácidos Linoleicos/administración & dosificación , Ácidos Linoleicos/sangre , Lípidos/sangre , Masculino , Persona de Mediana EdadRESUMEN
A 50 year-old woman with progressive systemic sclerosis accompanied by interstitial pneumonia complained of a dry cough. A variety of antitussive agents were given for the dry cough over a one year period, but her symptoms continued. However, when a herbal medicine Bakumondo-to was administered, her intractable dry cough subsided dramatically within 10 days. Bakumondo-to may be a good antitussive agent for interstitial pneumonia associated with a dry cough that is resistant to other antitussives.
Asunto(s)
Agonistas Adrenérgicos beta/farmacología , Antitusígenos/farmacología , Tos/tratamiento farmacológico , Medicamentos Herbarios Chinos/farmacología , Fitoterapia , Femenino , Humanos , Persona de Mediana EdadRESUMEN
This paper describes effects of (2"R)-4'-O-tetrahydropyranyladriamycin hydrochloride (THP) on perinatal and postnatal rats. The drug was administered intravenously to female rats at 0.01, 0.03 or 0.1 mg/kg daily from day 17 of pregnancy to 21 days after delivery. Results were described below. At any dose levels tested, THP did not affect the body weight gain, food and water consumption by pregnant rats, and length of gestation period or delivery rate. However, at the highest dose level, THP decreased spleen weight. THP, at any dose levels, did not have toxic effect on development, physiological functions, behavior, mating, fertility or pregnancy of the first generation offspring (F1). At the highest dose of 0.1 mg/kg, however, THP produced delayed ossification of sacrococcygeal vertebra in the second generation fetuses (F2). The results suggest that the maximum "no effect" dose of THP to pregnant rats and offsprings is 0.03 mg/kg/day intravenously.
Asunto(s)
Animales Recién Nacidos/crecimiento & desarrollo , Antibióticos Antineoplásicos/toxicidad , Doxorrubicina/análogos & derivados , Preñez/efectos de los fármacos , Reproducción/efectos de los fármacos , Animales , Antibióticos Antineoplásicos/administración & dosificación , Conducta Animal/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Doxorrubicina/administración & dosificación , Doxorrubicina/toxicidad , Ingestión de Líquidos/efectos de los fármacos , Ingestión de Alimentos/efectos de los fármacos , Desarrollo Embrionario y Fetal/efectos de los fármacos , Femenino , Inyecciones Intravenosas , Masculino , Tamaño de los Órganos/efectos de los fármacos , Embarazo , Ratas , Ratas EndogámicasRESUMEN
A perinatal and postnatal study of MT-141 was performed in SD rats. The dams were administered intramuscularly (i.m.) with MT-141 at the dose levels of 400, 800 and 1,600 mg/kg/day from the day 17 of gestation until the day 21 post delivery. The results are summarized as follows. No significant adverse effects of MT-141 were observed on the body weight gain, food consumption and water intake in dams of all groups treated with the drug during the perinatal and postnatal period. MT-141 did not change parameters of reproductive study in birth, development, physiological function and behavior of F1 rat. This compound had no effect on the fertility in F1 rats and also did not caused significant defects in the external appearance, viscera and skeleton of fetuses from dams (F1). It is concluded from these results that the maximal "no effective" dose of MT-141 is above 1,600 mg/kg/day i.m. for dams and the offsprings.
Asunto(s)
Cefamicinas/farmacología , Fertilización/efectos de los fármacos , Animales , Peso al Nacer/efectos de los fármacos , Implantación del Embrión/efectos de los fármacos , Femenino , Trabajo de Parto/efectos de los fármacos , Hígado/anatomía & histología , Masculino , Tamaño de los Órganos/efectos de los fármacos , Embarazo , Ratas , Ratas EndogámicasAsunto(s)
Ácidos Docosahexaenoicos/administración & dosificación , Hostilidad , Adulto , Envejecimiento , Femenino , Aceites de Pescado/administración & dosificación , Humanos , Masculino , Persona de Mediana Edad , Ensayos Clínicos Controlados Aleatorios como Asunto , Estrés Psicológico/complicacionesRESUMEN
BACKGROUND: It was shown that a traditional Chinese medicine, Hochu-ekki-to (HET), had adjuvant effects in influenza vaccination in an animal experiment. This, however, could not be assessed in a clinical study. METHODS: Thirty-two healthy subjects were randomly assigned to two groups (control and HET groups) in a double-blind manner. HET subjects (n=17) took 7.5 g of HET/day for two weeks; control subjects took the same amount of indistinguishable placebo. Then subjects were vaccinated against influenza (H1N1, H3N2 and B/Shandong). Hemagglutinin titers and natural killer (NK) activity were measured at weeks 0, 1, 2, 4, and 12. RESULTS: Antiinfluenza titers against the three viruses were increased continuously for the first two weeks and leveled off. However, there were no significant differences in any titers between the two groups. NK activity peaked at week 2 without any inter-group differences. CONCLUSION: We could not find any adjuvant effects of HET in this experimental condition.
Asunto(s)
Adyuvantes Inmunológicos/uso terapéutico , Suplementos Dietéticos , Medicamentos Herbarios Chinos , Vacunas contra la Influenza/inmunología , Gripe Humana/prevención & control , Extractos Vegetales/uso terapéutico , Adulto , Anticuerpos Antivirales/biosíntesis , Método Doble Ciego , Femenino , Pruebas de Inhibición de Hemaglutinación , Humanos , Subtipo H1N1 del Virus de la Influenza A/inmunología , Subtipo H3N2 del Virus de la Influenza A/inmunología , Masculino , Persona de Mediana Edad , Resultado del Tratamiento , VacunaciónRESUMEN
Thermospray liquid chromatography/tandem mass spectrometry provides a sensitive and convenient technique for the structural analysis of oxygenated polyunsaturates. Analysis of pentafluorobenzyl derivatives in the negative ion mode under the filament- or discharge-on condition generated abundant [M - PFB]- ions. These ions were further fragmented by collision with argon and detected in the negative ion mode. The negative ion fragmentation pattern was examined for various oxygenated polyunsaturated fatty acid standards as well as their deuterated and/or hydrogenated forms. Characteristic fragmentation occurs at the oxygenated C-C bonds, allowing unambiguous determination of the sites of oxygenation. The sample amount required is typically in the low tens of nanogram range. Using this method the structures of epoxy, hydroxy derivatives of 4,7,10,13,16,19-docosahexaenoic acid (22:6w3) formed by soybean lipoxygenase were determined. They were 13-hydroxy-16,17-epoxy-22:5w3 and 15-hydroxy-16,17-epoxy-22:5w3.
Asunto(s)
Ácidos Grasos/análisis , Ácido 12-Hidroxi-5,8,10,14-Eicosatetraenoico , Ácidos Araquidónicos/análisis , Cromatografía Líquida de Alta Presión , Ácidos Hidroxieicosatetraenoicos/análisis , Lipooxigenasa/metabolismo , Espectrometría de MasasRESUMEN
It has been previously claimed that rodent brain possesses lipoxygenase activity, based upon the structure of products which were formed from arachidonic acid and the inhibition of this activity by "lipoxygenase inhibitors." Our studies confirm that various positional isomers of hydroxyeicosatetraenoic acids (HETE) are formed (e.g., 15-, 12-, 11-, 9-, 8- and 5-HETE) by brain homogenate and that their production is inhibited by certain lipoxygenase inhibitors, such as nordihydroguaiaretic acid (NDGA) but not by cyclooxygenase or cytochrome P-450 inhibitors. However, stereochemical analysis indicated racemic distributions of these products suggesting that they were not formed by a lipoxygenase enzyme but rather by a peroxidative process. It should also be noted that the presence of 12(S)-lipoxygenase activity could be demonstrated by stereochemical analysis only when the brain was not perfused properly, indicating this activity was due to blood cell contamination. It is known that many lipoxygenase inhibitors are also capable of inhibiting peroxidative reactions apparently due to their free radical scavenging properties. For these reasons, it is essential that the stereochemical purity of purported lipoxygenase products be determined and that previous claims of lipoxygenase activity in mammalian brain be reexamined.
Asunto(s)
Encéfalo/metabolismo , Ácidos Hidroxieicosatetraenoicos/metabolismo , Lipooxigenasa/metabolismo , Ácido 5,8,11,14-Eicosatetrainoico/farmacología , Animales , Ácido Araquidónico , Ácidos Araquidónicos/metabolismo , Cromatografía Líquida de Alta Presión , Sistema Enzimático del Citocromo P-450/aislamiento & purificación , Sistema Enzimático del Citocromo P-450/metabolismo , Ácidos Hidroxieicosatetraenoicos/aislamiento & purificación , Indometacina/farmacología , Cinética , Lipooxigenasa/aislamiento & purificación , Masculino , Masoprocol/farmacología , Metoxaleno/farmacología , Proadifeno/farmacología , Prostaglandina-Endoperóxido Sintasas/aislamiento & purificación , Prostaglandina-Endoperóxido Sintasas/metabolismo , Ratas , Ratas EndogámicasRESUMEN
Based on the inhibitor profile, production rate, and stereochemical purity of the hydroxylated products, it was demonstrated that lipoxygenation in rat brain occurs only in the pineal. Both positional and stereochemical specificities of the hydroxylation were observed only in pineal, clearly indicating that only the pineal is capable of lipoxygenating polyunsaturated fatty acids among the rat brain regions examined. Cerebral cortex also produced hydroxy products; however, they were racemic mixtures, indicating that peroxidation was responsible for their production. Rat pineal homogenate, obtained after the brain was perfused, metabolized [14C]docosahexaenoic acid ([1-14C]22:6n3) to monohydroxy derivatives, primarily by the 12- and, to a lesser extent, by the 15-lipoxygenase (LO) reaction. The resulting metabolites were 14(S)- and 17(S)-hydroxydocosahexaenoic acid (HDoHE), as determined by reversed-phase HPLC, chiral-phase HPLC, thermospray liquid chromatography-mass spectrometry, and gas chromatography-mass spectrometry. Because blood was removed by perfusion of the brain before incubation, it was clear that the observed LO activity was not due to contamination with blood cell components. The production rate of 17-HDoHE from 22:6n3 was higher than that of 15-hydroxyperoxy-5,8,11,13-eicosatetraenoic acid from 20:4n6, whereas 12-LO activity toward these two substrates was comparable. These monohydroxy metabolites were also detected in the pineal body lipid extract using negative ion chemical ionization mass spectrometry. This is the first observation of endogenous production of hydroxylated compounds in pineal. The ratio of endogenous 15-LO to 12-LO products was considerably higher than that of the in vitro production from exogenous substrate. In some cases, 15-LO products were the major LO metabolites present in the lipid extract of pineal body for both 20:4n6 and 22:6n3. Both 12- and 15-LO activities were recovered mainly in the microsomal plus cytosolic fraction. In addition to monohydroxy products, epoxy, hydroxy derivatives were formed from 22:6n3 by the pineal. The major isomer was identified as 12-hydroxy-13,14-epoxy-22:5n3.