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PubMed1979

Regulation of body cholesterol pools. Influence of cholesterol input and excretion in an animal model.

Biliary cholesterol excretion closely parallels lecithin excretion in the rat and may be increased by feeding an excess of choline and decreased by choline deficiency. To determine the relative influence of cholesterol input and excretion on whole body cholesterol metabolism, we have measured by compartmental analysis rates of cholesterol transport and pool sizes when both input and choline-mediated biliary excretion were increased and diminished. In choline-deficient animals with impaired excretion, plasma cholesterol was reduced. However, in deficient animals more cholesterol was transported into the slowly exchanging pool to increase pool size, and, when input was increased (by addition of cholesterol to diet), the slowly exchanging pool was even more markedly enlarged. In contrast, when excess choline was fed, plasma cholesterol was increased but excretion so exceeded transport into the slowly exchanging pool that pool size was actually reduced. Furthermore, in choline-fed animals with unimpaired excretion, addition of cholesterol to the diet to increase input did not result in pool expansion. Thus, in this model, cholesterol excretion and tissue deposition were reciprocally related, and, regardless of plasma cholesterol concentration and cholesterol input, stores were found to increase only when biliary excretion was impaired.

Animals↗

PubMed1981

Urinary excretion of C4--C10-dicarboxylic acids and antiketogenic properties of adipic acid in ketogenic-stimulated rats due to diabetes, long-chain and short-chain monocarboxylic acids.

The urinary excretion of C4--C10-dicarboxylic acids (succinic, adipic, suberic and sebacic acids) and the antiketogenicity of adipic acid have been studied in ketogenic-stimulated rats in three biochemically different states: diabetes, fat-feeding (long-chain monocarboxylic acids) and feeding of hexanoic acid (short-chain monocarboxylic acid). In diabetic rats urinary excretions of adipic and suberic acids were elevated before the rise in urinary excretions of 3-hydroxybutyric acid, i.e. before ketosis appeared. In severe diabetic ketosis sebacic acid was below normal values, whereas the excretion of succinic acid was unaltered. Rats, in which ketosis was provoked by hexanoic acid, had preketotic high urinary excretions of adipic and succinic acids. After ketosis the excretions of succinic acid declined again whereas the excretion of adipic acid rose further, together with that of suberic acid. Moreover, when rats which were ketotic due to treatment with long-chain triacylglycerol or hexanoic acid received 500 mg of adipic acid the urinary excretion of succinic acid rose significantly. However, no changes in succinic acid excretion were seen in diabetic ketotic rats treated with the same amount of adipic acid. Exogenously administered adipic acid was strongly antiketogenic towards ketosis caused by long-chain or short-chain monocarboxylic acids, but had no effect on diabetic ketosis.

Acidosis↗

PubMed1985

Biliary excretion and enterohepatic circulation of 1-nitropyrene metabolites in Fischer-344 rats.

1-Nitropyrene (1-NP), present in diesel engine emissions, is a potent mutagen to bacteria, such as those found in mammalian intestinal tract, which contain nitroreductase enzymes. The purposes of this study were to determine the importance of bile as a route of excretion of 1-NP metabolites and to determine if reabsorption of biliary metabolites required the presence of intestinal bacteria. The bile ducts of male Fischer-344 rats were cannulated, 0.3 or 1.2 mumoles [3H]1-NP was given i.v., and bile, urine, and feces were collected for 24 hr. Biliary excretion accounted for 70 (80%) or 170 (60%) nmoles of [3H]1-NP after the low and high dose, respectively, with half-times for excretion of 1.7 hr +/- 0.3 (+/- S.E.M.) and 3.4 hr +/- 1.6 (+/- S.E.M.). Excretion of [3H]1-NP equivalents in the urine was linearly related to dose, with 6 or 16 nmoles (8%) excreted in 24 hr. At the low dose, more radioactivity appeared in the urine in control rats compared to bile-duct cannulated rats, suggesting that reabsorption of 1-NP metabolites occurred. Pretreatment of rats with orally administered antibiotics prior to i.v. injection of 0.3 mumole [3H]1-NP decreased radioactivity excreted in urine compared to untreated controls, suggesting that intestinal microorganisms may alter the biliary metabolites of 1-NP to facilitate reabsorption. Pretreatment of rats with buthionine sulfoximine, a glutathione depletor, decreased the excretion of certain biliary metabolites, suggesting that they were mercapturic acids of 1-NP metabolites. In summary, the results of these studies indicate that bile was an important route of excretion of nitropyrene metabolites. A portion of the excreted metabolites was reabsorbed from the gut, and this reabsorption required the presence of gut microorganisms.

Animals↗

PubMed1990

Comparison of endogenous and radiolabeled bile acid excretion in patients with idiopathic chronic diarrhea.

Fecal recovery of radioactivity after ingestion of a bolus of radiolabeled bile acid is abnormally high in most patients with idiopathic chronic diarrhea. To evaluate the significance of this malabsorption, concurrent fecal excretion of both exogenous radiolabeled bile acid and endogenous (unlabeled) bile acid were measured in patients with idiopathic chronic diarrhea. Subjects received a 2.5-microCi oral dose of taurocholic acid labeled with 14C in the 24th position of the steroid moiety. Endogenous bile acid excretion was measured by a hydroxysteroid dehydrogenase assay on a concurrent 72-h stool collection. Both radiolabeled and endogenous bile acid excretion were abnormally high in most patients with chronic diarrhea compared with normal subjects, even when equivoluminous diarrhea was induced in normal subjects by ingestion of osmotically active solutions. The correlation between radiolabeled and endogenous bile acid excretion was good. However, neither radiolabeled nor endogenous bile acid excretion was as abnormal as is typically seen in patients with ileal resection, and none of these diarrhea patients responded to treatment with cholestyramine with stool weights less than 200 g. These results suggest (a) that this radiolabeled bile acid excretion test accurately reflects excess endogenous bile acid excretion; (b) that excess endogenous bile acid excretion is not caused by diarrhea per se; (c) that spontaneously occurring idiopathic chronic diarrhea is often associated with increased endogenous bile acid excretion; and (d) that bile acid malabsorption is not likely to be the primary cause of diarrhea in most of these patients.

Adult↗

PubMed1995

Characteristics of individuals who excrete versus retain sodium under stress.

To examine the role of stress on renal sodium excretion, we studied 27 normotensive and 21 hypertensive subjects. All subjects were placed on a standardized sodium diet. After water loading (2290 ml in 3 1/2 hr) they completed a 30 min baseline and a 30 min stress period (competitive videogame). Sixty-nine percent of the subjects increased ("excreters") and 31% decreased ("retainers") their sodium excretion under stress. In addition to increased potassium excretion (p < 0.006), excreters also manifested less of a stress associated increase in systolic (p = 0.055) and diastolic (p = 0.040) blood pressure and showed greater expression of anger (p < 0.02) than retainers. The same subjects were also studied to determin the effects of angiotensin converting enzyme inhibition (captopril 25 mg b.i.d.) on sodium excretion. On captopril, excreters now showed a retention of sodium (p < 0.001) and potassium (p < 0.01) under stress and no longer differed significantly in blood pressure reactivity. The results suggest that there are two different stress-related patterns of renal sodium excretion, that these patterns are related to blood pressure responses to stress, and may be related to anger expression. In addition, sodium excretion patterns under stress may be altered with certain type of antihypertensive medications.

Adult↗

PubMed1978

Abnormal epinephrine urinary excretion in Parkinsonians: correction of the disorder by levodopa administration.

Epinephrine (E) and norepinephrine (NE) as well as vanilmandelic acid (VMA) urinary excretion was investigated in 54 patient with Parkinsonism and 29 controls. In Parkinsonians the mean value of NE excretion was normal, while that of E was significantly higher than in controls (P less than 0.001). Analysis of results in terms of age showed that only the patients in the 5th and 6th decades displayed significant increases in E excretion when compared to age-matched controls. No age-group differences were found for NE excretion. VMA was significantly higher in Parkinsonians than in controls. Both in Parkinsonians and in controls VMA excretion correlated significantly with that of NE but not with the E excretion. Ten-day treatment with levodopa (1.5 g/day) of Parkinsonians below the age of 60 was followed by a constant decrease in the excretion of E and a less consistent, nonsignificant increase in the excretion of NE. The abnormality of E excretion noticed in younger Parkinsonians suggests involvement in the pathologic process, of adrenal medulla, the main site of E synthesis.

Adult↗

PubMed1976

Bound hydroxyproline excretion following gelatin loading in prolidase deficiency.

The excretion of peptide-bound hydroxyproline before and after gelatin loading was evaluated in two children with prolidase deficiency, two adult heterozygotes, and normal controls. On a low hydroxyproline diet, the patients with prolidase deficiency excreted 6.9 and 2.4 times more bound hydroxyproline than normal children. The bound hydroxyproline excretion for the heterozygotes was comparable to the adult controls. Children ingested 20 g of gelatin and adults 29 g. In the 24 hr following gelatin loading, the homozygotes excreted 14.4 and 17.3 times more of the ingested load of hydroxyproline than did normal children. This constituted 39% and 47% of the hydroxyproline ingested. Of the hydroxyproline excreted in 24 hr, 58%, and 61.4% was excreted in the first 6 hr. Over the 24 hr period, the normal children excreted 2.7% of the hydroxyproline ingested (97.8% in the first 6 hr). The heterozygotes excreted only slightly more than the adult controls. The normal adults excreted 6.0% of the ingested hydroxyproline (82.8% in the first 6 hr). In prolidase deficiency, large amounts of peptide-bound hydroxyproline can cross the intestinal wall unhydrolyzed. Prolidase appears to have an important role in normal hydrolysis of peptide-bound hydroxyproline.

Adult↗

PubMed1987

The effect of saccharin ingestion on the excretion of microbial amino acid metabolites in rat and man.

Low dietary levels of sodium saccharin (0-2%) fed to male rats for 6 weeks produced a dose-related increase in the urinary excretion of p-cresol, a major microbial metabolite of tyrosine. Some animals fed higher levels of saccharin (5-7.5%) for 6 weeks excreted increased amounts of p-cresol, but many excreted negligible amounts so that the overall dose-response relationship was bell shaped. After 20 weeks of exposure, all rats in the higher dose groups showed increased p-cresol excretion and by 26 weeks the 7.5% saccharin group showed a 36-fold increase over animals fed the 0% saccharin diet. The urinary excretion of phenol, another microbial amino acid metabolite, was constant in animals fed dietary levels of saccharin below 2% for 6 weeks, but was virtually abolished at higher levels. The excretion of indican (formed from indole, a microbial metabolite of tryptophan) was increased by saccharin in a dose-related fashion at all time points, but showed only a 3-fold increase at 7.5% compared with the 0% group. p-Cresol may therefore prove more sensitive than indican as an indicator of altered microbial metabolism due to saccharin. In a separate study the effect of 7.5% saccharin on p-cresol and indican excretion was shown to be largely reversible and the excretion of phenol increased rapidly when saccharin was withdrawn from the diet. Chronic saccharin administration to man at high doses (1 g/day for 4 weeks) had no perceptible effect on the excretion of these three metabolites.

Amino Acids↗

PubMed1988

Species variations in biliary excretion of glutathione-related thiols and methylmercury.

The biliary excretion of methylmercury is thought to be related to the biliary excretion of nonprotein thiols in rats. Species differences in biliary excretion of glutathione (GSH) and related thiols are unknown; therefore, the relationship between the biliary excretion of GSH-related thiols and methylmercury in five species was studied. The biliary excretion rate of GSH-related thiols and disulfides was 369, 192, 94, 50, and 19 nmol/min/kg for mice, rats, hamsters, guinea pigs, and rabbits, respectively. The main thiol in mouse, hamster, and rat bile was GSH, whereas guinea pig and rabbit bile contained mainly cysteinylglycine (Cys-Gly). The larger percentage of Cys-Gly in guinea pig and rabbit bile was correlated with their greater hepatic gamma-glutamyltranspeptidase (GGT) activity than that observed in the other species. The biliary excretion rate (nmol/min/kg) of methylmercury was approximately 0.8 in mice, rats, and hamsters compared to significantly lower rates in guinea pigs and rabbits (0.15 and 0.03, respectively). It is concluded that the species-specific composition of GSH-related thiols and disulfides in bile is related to species variations in hepatic GGT activity, and that the species variation in biliary excretion of GSH-related thiols does not entirely account for the species variation in methylmercury excretion, indicating other factors are also apparently involved in determining the rate of biliary excretion of methylmercury.

Animals↗

PubMed1978

Urinary prostaglandin E excretion: effect of chronic alterations in sodium intake and inhibition of prostaglandin synthesis in the rabbit.

On the basis of acute experiments in animals, a role for prostaglandin E (PGE) in the regulation of urinary sodium excretion has been suggested. Limited information is available, however, concerning the possible role of PGE in chronic adjustments to sodium intake. These studies were designed to determine whether chronic changes in sodium balance would modify renal PGE excretion and whether partial inhibition of prostaglandin synthesis would alter the ability of the kidney to adjust to an alteration in sodium intake. Thus, we measured sodium and PGE excretion in rabbits on chronic high and low salt diets before and after inhibition of prostaglandin synthesis with indomethacin or meclofenamate. Although the alterations in salt intake resulted in large changes in sodium excretion there was no significant change in urinary PGE excretion. After administration of either indomethacin or meclofenamate for several days there was a significant fall in PGE excretion, but no significant change in sodium excretion. These results suggest that in the rabbit 1) chronic changes in sodium excretion can occur without modifying PGE excretion (and presumably renal PGE synthesis) and 2) inhibition of PGE synthesis does not impair the kidney's ability to adjust to a chronic high or low sodium intake.

Animals↗

PubMed1993

Effect of water deprivation, desmopressin (DDAVP) infusion, and oral loads of water, Na+ and NH4+ on urinary excretion of epidermal growth factor in the rat.

UNLABELLED: Epidermal growth factor (EGF) is synthesized in the kidneys and excreted in urine. Administration of exogenous EGF modulates the reabsorption of Na+ and the vasopressin stimulated reabsorption of water in the collecting tubules. In order to clarify whether this reflects a physiological role for urinary EGF we examined the effects of changes in the oral loads of water, Na+ and NH4+ as well as the effect of infusion of the vasopressin analogue, desmopressin (DDAVP) on the endogenous urinary EGF excretion in the rat. Water deprivation for 48 h reduced the urinary excretion of EGF by 25% and the urinary EGF/creatinine ratio by 8%. Also, urinary volume, Na+ excretion, and urinary pH were reduced by water deprivation. Infusion of DDAVP, low plasma vasopressin induced by polydipsia, and changes in the renal excretion of Na+ and H+ did not affect the urinary excretion of EGF. IN CONCLUSION: it seems unlikely that nephrogenous EGF excreted in the urine plays a physiological role in the regulation of the renal excretion of Na+ and H+ and in the vasopressin stimulated reabsorption of water in the rat. However, since water deprivation reduced the urinary excretion of EGF it remains possible that urinary EGF plays a role in the complex physiological response to dehydration.

Administration, Oral↗

PubMed1988

Factors associated with cytomegalovirus excretion in hospitalized children.

Hospital employees, especially pregnant women, have expressed concern over exposure to patients excreting cytomegalovirus (CMV). However, the vast majority of CMV excreters are asymptomatic and are not identified while hospitalized. As part of a 2-year, longitudinal study of nosocomial transmission of CMV in a children's hospital, the prevalence rates of CMV excretion by patients in different areas of the hospital were determined. The average prevalence rates were neonatal intensive care unit, 5.7%; intermediate care nurseries, 4%; premature nursery, 6.3%; normal newborn nursery, 3%; hematology-oncology, 3.7%; pediatric intensive care unit, 3.6%; general pediatric ward, 6%; and a chronic care unit, 16%. During this 2-year study, 315 patients admitted to the chronic care unit were investigated to determine which clinical factors might help predict children likely to excrete CMV. With the use of multiple logistic regression analysis of variables, prior excretion of CMV, multiple hospital admissions, female sex, and Hispanic ethnic background were correlated with excretion. Although not identified as significant factors, a history of premature, bronchopulmonary dysplasia and positive results of CMV serologic studies were more commonly associated with excretion. CMV excretion occurred in all areas within a children's hospital, and certain factors were associated with excretion, but it is unlikely that this information could adequately identify "safe" patients or safe areas within a hospital. This study reinforces the need to follow proper precautions with all patients.

Adult↗

PubMed1992

Fecapentaene excretion and fecal mutagenicity in relation to nutrient intake and fecal parameters in humans on omnivorous and vegetarian diets.

Fecapentaenes are strong fecal mutagenic compounds presumably occurring in the majority of Western human individuals, and are possibly essential initiators of colon carcinogenesis. Dietary factors have been shown to influence colorectal cancer risk and to modulate both fecal mutagenicity and fecapentaene concentrations. Therefore, in this study, excretion of fecapentaenes is determined in humans consuming either vegetarian or omnivorous diets. The results show that the most predominant fecapentaene forms are excreted in higher concentrations by vegetarians. Consumption of cereal fiber, calcium and carotene as well as fecal concentrations of iso-lithocholic acid were found to correlate positively with excreted concentrations of one or more fecapentaene analogues. On average, 22% of excreted fecapentaene concentrations was found to be related to nutrient intake in stepwise regression models. Dietary calcium intake was found to be the most significant factor positively correlating with excreted fecapentaene concentrations. Intake of mono-unsaturated fatty acids or fiber from vegetables and fruit could be shown to correlate with fecapentaene excretion to a lesser degree. Despite high fecapentaene concentrations in fecal dichloromethane extracts, only 1 out of 20 samples revealed significant mutagenic activity in Salmonella typhimurium TA 100. Further, aqueous extracts of feces from omnivores appeared to be equally mutagenic as feces from vegetarians and contained non-detectable concentrations of fecapentaenes. It is concluded that dietary factors do affect excreted fecapentaene levels, but only to a relatively minor extent. Since vegetarians at low risk for colorectal cancer excrete higher concentrations of fecapentaenes, it could be hypothesized that relatively increased fecapentaene excretion in combination with antimutagenic compounds in feces represents colon cancer prevention.

Bile Acids and Salts↗

PubMed2005

Urinary-peptide excretion by patients with and volunteers without diabetes.

Large quantities of peptides (1-4 g) are excreted in human urine each day. In this study we sought to analyze how peptide excretion varies with increasing albuminuria associated with diabetes, as well as to characterize the size distribution of albumin-derived peptides in urine from volunteers without diabetes and from patients with macroalbuminuria and diabetes. We detected albumin-derived peptides by injecting tritiated albumin intravenously into human volunteers and patients with diabetes. Urine was collected after 24 hours and fractionated on a size-exclusion column. This fractionation revealed peptides with molecular weights ranging from 300 to 500 Da in volunteers without diabetes. The albumin-derived peptides were of higher molecular weight in the urine of a patient with macroalbuminuria and diabetes. The molecular-weight distribution of the peptides derived from tritiated albumin peptides was paralleled by the distribution of all protein peptides (including albumin) as determined with the use of the Biuret protein assay or absorbance at 214 nm. We determined peptide-excretion rates by filtering urine from patients with diabetes through a 10,000 Da molecular-weight-cutoff membrane and then measuring the filtrate with the use of the Biuret assay. This analysis revealed that the peptide-excretion rate increased with increasing total protein excretion, regardless of whether the patient demonstrated normoalbuminuria or microalbuminuria. Among patients with macroalbuminuria, the peptide-excretion rate leveled off and even decreased in the face of an increasing albumin concentration or protein-excretion rate. This study confirms that albumin-derived and protein-derived peptides exist at high concentrations in urine. Although peptide-excretion rates are maintained at similar levels up to macroalbuminuric states, the relative proportion of peptide excretion is significantly reduced compared with total protein.

Albumins↗

PubMed1995

Urinary isoflavonoid phytoestrogen and lignan excretion after consumption of fermented and unfermented soy products.

OBJECTIVE: To compare the effects of consumption of fermented and unfermented soy products on excretion of urinary isoflavonoid phytoestrogens and lignans in healthy men. DESIGN: A randomized, crossover trial consisting of two 9-day feeding periods following 5 days of baseline data collection. SUBJECTS: Healthy men, aged 20 to 40 years, were recruited from the University of Minnesota Twin Cities community. Of the 22 subjects who began the study, 17 completed all feeding periods. INTERVENTIONS: Fermented soy product (112 g tempeh) or unfermented soy (125 g soybean pieces) was consumed during each controlled feeding period. MAIN OUTCOME MEASURE: Urine samples collected while subjects consumed their habitual diets and on the last 3 days of each feeding period were analyzed for isoflavonoid and lignan content by isotope dilution gas chromatography-mass spectrometry. STATISTICAL ANALYSIS PERFORMED: Comparisons of isoflavonoid and lignan excretion were analyzed using the general linear model procedure. Orthogonal contrasts were used to determine treatment differences of interest. RESULTS: Urinary excretion of isoflavonoids (equol, O-desmethylangolensin [O-DMA], daidzein, genistein) was higher and excretion of lignans (enterodiol, enterolactone) was lower when subjects consumed soy-supplemented diets than when they consumed their habitual diets (P < .05). Urinary isoflavonoid excretion and lignan excretion were similar when subjects consumed tempeh and soybean pieces diets; however, recovery of daidzein and genistein was significantly higher when subjects consumed the tempeh diet than when they consumed the soybean pieces diet (P < .002). When fed soy, 5 of 17 subjects excreted high amounts of equol. These five subjects tended to excrete less O-DMA and daidzein than the 12 subjects who excreted low amounts of equol (P < .06). CONCLUSIONS: Fermentation of soy decreased the isoflavone content of the product fed but increased the urinary isoflavonoid recovery. This finding suggests that fermentation increases availability of isoflavones in soy.

4-Butyrolactone↗

PubMed2002

Environmental lead exposure and urate excretion in the general population.

PURPOSE: Chronic occupational exposure to lead is related to low urate excretion and a high incidence of gout in lead workers. However, whether chronic low-level environmental lead exposure influences urate excretion in the general population remains unknown. SUBJECTS AND METHODS: We studied 111 healthy subjects with normal renal function (serum creatinine level < or =1.4 mg/dL) and no previous lead exposure or systemic diseases. All subjects had their blood lead levels measured, received ethylenediaminetetraacetic acid mobilization tests to assess their body lead burdens, and were investigated for renal function and urate excretion to assess the relation between lead and urate excretion. We studied urate excretion before and after lead chelation therapy in 24 subjects with high-normal body lead burden (>78 mg and <600 mg). RESULTS: Healthy subjects with gout (n = 27) manifested a higher body lead burden (84 +/- 42 mg vs. 45 +/- 30 mg, P <0.0001) and lower urate clearance (3.7 +/- 1.2 mL/min/1.73 m(2) vs. 6.0 +/- 2.8 mL/min/1.73 m(2), P <0.0001) than did those without gout (n = 84). Blood lead levels and body lead burden of all subjects were within the safe range. In analyses that adjusted for age, sex, body mass index, protein intake, and creatinine clearance, blood lead level was significantly related to serum urate level (beta coefficient [+/- SE] = 0.23 +/- 0.11, P = 0.03), and body lead burdens were related to all indices of urate excretion (serum urate: beta coefficient = 0.023 +/- 0.005, P <0.0001; daily urate excretion: beta coefficient = -1.55 +/- 0.40, P = 0.0002; urate clearance: beta coefficient = -0.030 +/- 0.006, P <0.0001; fractional urate excretion: beta coefficient= -0.034 +/- 0.006, P <0.0001). Following lead chelation therapy, urate clearance increased after body lead burden was reduced (3.4 +/- 1.2 mL/min/1.73 m(2) vs. 4.9 +/- 1.4 mL/min/1.73 m(2), P <0.005). CONCLUSION: Chronic low-level environmental lead exposure may inhibit urate excretion in the general population, and lead chelation therapy reduces this inhibition. These findings support efforts to reduce sources of environmental lead exposure and suggest alternative approaches to hyperuricemia and gout in the general population.

Adult↗

PubMed1999

Urinary excretion of biomarkers for radical-induced damage in rats treated with NDMA or diquat and the effects of calcium carbimide co-administration.

The urinary excretion of seven aldehydes, acetone, coproporphyrin III and 8-hydroxy-2'-deoxyguanosine (8-OH-dG) as non-invasive biomarkers of oxidative damage was measured in rats treated with diquat or N-nitrosodimethylamine (NDMA), two compounds causing hepatic damage by different mechanisms. Furthermore, the effect of co-administration of the aldehyde dehydrogenase inhibitor, calcium carbimide (CC) on the urinary excretion of the aldehydes was determined. Slight hepatotoxicity was found at the end of the experiment after treatment with NDMA (0.5, 4 and 8 mg/kg at t = 0, 48 and 96 h, respectively) or diquat (6.8 and 13.6 mg/kg at t = 0 and 48 h, respectively). In diquat treated rats slight nephrotoxicity was also found. Urinary excretion of aldehydes, acetone and coproporphyrin III remained largely unchanged in rats treated with NDMA. In the rats treated with diquat, the urinary excretion of several aldehydes was several-fold increased. An increase was also found in the urinary excretion of 8-OH-dG after the second dose of diquat. Treatment of rats with CC did not significantly influence the urinary excretion of aldehydes in control and NDMA rats. However, in rats treated with diquat, CC caused a potentiating effect on the excretion of acetaldehyde, hexanal and malondialdehyde (MDA), indicating that oxidation of aldehydes to carbonylic acids by aldehyde dehydrogenases (ALDHs) might be an important route of metabolism of aldehydes. In conclusion, increased urinary excretion of various aldehydes, acetone, coproporphyrin III and 8-OH-dG was observed after administration of diquat, probably reflecting oxidative damage induced by this compound. No such increases were found after NDMA administration, which is consistent with a different toxicity mechanism for NDMA. Therefore, excretion of aldehydes, acetone, coproporphyrin III and 8-OH-dG might be used as easily accessible urinary biomarkers of free radical damage.

8-Hydroxy-2'-Deoxyguanosine↗

PubMed2000

Effect of gamma-L-glutamyl-L-dopa on phosphate excretion.

gamma-L-glutamyl-L-DOPA (gludopa) is a dopamine prodrug that is relatively specific for the kidney. Because dopamine is phosphaturic, the present study compared the phosphaturic effects of the infusion of equimolar doses of gludopa (n = 8), L-DOPA (n = 8), and gamma-L-glutamyl-L-tyrosine (glutyrosine, n = 6). Glutyrosine was used as a control to evaluate the effect of the glutamyl portion of gludopa on phosphate excretion. Sprague-Dawley rats (350 to 400 g) were anesthetized with 5-sec-butylethyl-2-thyobarbituric acid (Inactin; 100 mg/kg, IP) and underwent thyroparathyroidectomy. Clearances were taken during the infusion of normal saline vehicle, followed by the infusion of gludopa, L-DOPA, or glutyrosine, all infused at the rate of 10 nmol/kg bolus and 0.8 nmol/kg/min (iv). To determine the contribution of glutamyl derivative to phosphate excretion, gludopa or L-DOPA was infused in the presence of SCH23390, a DA-1 receptor antagonist. Gludopa infusion significantly increased dopamine excretion (from 1.9+/-0.2 ng/min to 17.0+/-3.9 ng/min, delta15.0+/-3.9 ng/min, P < .008) and fractional excretion of phosphate (from 2.6%+/-0.6% to 34.8%+/-1.8%, delta32.0%+/-1.6%, P < .001). L-DOPA infusion significantly increased dopamine excretion (from 1.4+/- 0.4 ng/min to 9.7+/-1.6 ng/min, delta8.3+/-1.5 ng/min, P < .001) and fractional excretion of phosphate (from 1.7%+/-0.6% to 8.2%+/-2.0%, delta6.4%+/-1.5%, P < .004). Glutyrosine infusion significantly increased fractional excretion of phosphate (from 2.8%+/-0.8% to 17.5%+/-5.2%, delta14.6%+/-4.8%, P < .03) without changing dopamine excretion (delta0.5+/-0.2 ng/min). Infusion of gludopa in the presence of SCH23390 increased fractional excretion of phosphate (from 5.7%+/-2.5% to 12.6%+/-3.5%, delta6.8%+/-2.3%, n = 6, P < .03), whereas SCH23390 completely blocked the phosphaturic effect of L-DOPA. We conclude that gamma-L-glutamyl-L-DOPA is more phosphaturic than L-DOPA in the rat because of the combined effects of dopamine and the glutamyl moiety.

Animals↗