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R Fanelli

Publications and source records attributed to R Fanelli.

At least 109 records · Page 6Linked to original sources
PubMed1988

Mass spectrometric identification of urinary and plasma metabolites of 9-hydroxy-19,20-bis-nor-prostanoic acid (rosaprostol).

9-Hydroxy-19,20-bis-nor-prostanoic acid (Rosaprostol) is an antiulcer compound with antisecretory and cytoprotective action. We studied the metabolites of Rosaprostol found in human plasma and in human and rat urine. Sixteen different metabolites were tentatively identified on the basis of their mass spectra. Two presumed metabolites were synthesized. To clarify the identities of some of them, deuterated Rosaprostol was administered to rats and mass spectra of the deuterated and protonated metabolites were examined. Rosaprostol is metabolized following three metabolic pathways leading, combined, to oxidized compounds with a lower number of carbons than the parent drug.

Animals↗
PubMed1988

Effect of acute and chronic butylated hydroxyanisole administration on in vivo glucuronidation of N-nitrosobutyl(4-hydroxybutyl)amine in rats.

The urinary metabolic pattern of N-nitrosobutyl(4-hydroxybutyl)amine (NB4HBA) administered ip at a dose of 5 mg/kg body weight was studied in animals either pretreated with butylated hydroxyanisole (BHA) as a single oral dose of 50 or 250 mg/kg, or fed a diet containing 0.1 or 0.5% BHA. The 24-hr urinary excretion of NB4HBA, its glucuronic acid-conjugate (NB4HBA-G) and N-nitrosobutyl(3-carboxypropyl)amine (NB3CPA) in control rats were 0.12, 0.75 and 30% of the administered dose, respectively, and were not changed after a single oral dose of 50 mg BHA/kg. NB4HBA-G was significantly reduced in the urine of rats given 250 mg BHA/kg. In vitro assays carried out using rat-hepatic microsomal preparations as the source of the enzyme UDP-glucuronyl transferases (GT) and NB4HBA as the substrate, suggest that a competition between NB4HBA and BHA for the same enzyme may be the cause of the decreased NB4HBA-G excretion observed in vivo. A fourfold increase in NB4HBA-G urinary excretion was observed after chronic 0.5% BHA feeding; moreover, the glucuronic acid-conjugate of NB3CPA (NB3CPA-G), which was not detected in the controls or after acute BHA treatment, appeared in the urine of rats given dietary BHA for 3 wk, accounting for about 10% of the administered NB4HBA. In vitro experiments indicate that the increased glucuronides excretion may be the result of an elevated hepatic GT activity.

Animals↗
PubMed1988

Effect of butylated hydroxyanisole added in vitro or administered to rats on N,N-dibutylnitrosamine and N-butyl-N-(4-hydroxybutyl)nitrosamine metabolism by post-mitochondrial supernatant of liver homogenates.

The effect of butylated hydroxyanisole (BHA) on P-450-dependent omega-hydroxylation of N,N-dibutylnitrosamine (NDBA) to N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN), and the further oxidation of BBN to N-butyl-N-(3-carboxypropyl)nitrosamine (BCPN) by the alcohol/aldehyde dehydrogenase system was investigated using the post-mitochondrial supernatant of liver homogenates (S9) from acutely and chronically BHA pretreated animals or S9 fractions from untreated rats with BHA added. Acute oral BHA (50 and 250 mg.kg-1) did not change NDBA omega-oxidation, which was reduced by 35% only when the compound was administered 0.5% in the diet for 3 weeks. BCPN formation from BBN was unaffected by acute and chronic BHA pretreatment. In order to verify whether BHA or its metabolite(s) had a direct effect on NDBA and BBN oxidation, the compound was added to S9 fractions from untreated rats at various concentrations. Only when BHA concentrations were equimolar or in a 10-fold molar excess to the substrate concentration, we observed 30-50% inhibition of BBN formation and a reduced BCPN formation (60-80% of control values), from BBN. Thus, only at very high BHA concentrations could we confirm the inhibition of P-450-dependent mixed function oxidase and alcohol dehydrogenase activities involved in the metabolism of NDBA and BBN.

Administration, Oral↗
PubMed1987

Development of an experimental model for studying bladder carcinogen metabolism using the isolated rat urinary bladder.

The isolated rat urinary bladder was used to study this organ's capacity to metabolize chemical carcinogens. In our experimental conditions, the urinary bladder carcinogen N-nitrosobutyl(4-hydroxybutyl)amine was oxidized to N-nitrosobutyl(3-carboxypropyl)amine. A time-dependent increase was observed in the amount of N-nitrosobutyl(3-carboxypropyl)amine formed and simultaneous disappearance of N-nitrosobutyl(4-hydroxybutyl)amine added, indicating that the bladder can metabolize N-nitrosobutyl(4-hydroxybutyl)amine to the metabolite considered responsible for tumor induction in the urinary bladder of laboratory animals. At 15, 30, 60, and 120 min the percentages of N-nitrosobutyl(3-carboxypropyl)amine formed were 11, 22, 36, and 64%, respectively, and 62, 48, 37, and 26% of N-nitrosobutyl(4-hydroxybutyl)amine remained unchanged. When N-nitrosodibutylamine was introduced into the isolated urinary bladder and incubated for 120 min, its oxidized metabolites N-nitrosobutyl(4-hydroxybutyl)amine and N-nitrosobutyl(3-carboxypropyl)amine were formed, amounting to, respectively, 0.13 and 0.06% of the substrate added. The glucuronide of N-nitrosobutyl(4-hydroxybutyl)amine was incubated in the isolated rat urinary bladder both as a buffer and as a urine solution in order to detect cellular and urinary beta-glucuronidase activity. In both systems N-nitrosobutyl(4-hydroxybutyl)amine released was about 1% at 4 h and this percentage did not increase at 6 h. N-Nitrosobutyl(3-carboxypropyl)amine was detectable at 2 h and reached 0.2% of the substrate incubated at 6 h. The results indicate that the urinary bladder may play a role in activating bladder carcinogens.

Animals↗
PubMed1987

Antibody-mediated extraction/negative-ion chemical ionization mass spectrometric measurement of thromboxane B2 and 2,3-dinor-thromboxane B2 in human and rat urine.

An antibody-mediated extraction method for gas chromatographic-mass spectrometric analysis of thromboxane A2 (TXA2) urinary metabolites is reported. An antibody (Ab) raised against thromboxane B2 (TXB2) (35% cross-reacting with 2,3-dinor-TXB2) was coupled to CNBr-activated Sepharose 4B (Se) and used as stationary phase for simultaneous extraction of both compounds from urine. After addition of deuterium-labeled TXB2 as internal standard, rat or human urine was percolated through a small Ab-Se column. After being washed, the eluate was directly derivatized to the pentafluorobenzyl ester, methyloxime, and trimethylsilyl ether. Quantitation was performed by high-resolution gas chromatography-negative-ion chemical ionization mass spectrometry, monitoring the carboxylate anions. This method was applied to evaluate the urinary excretion of TXB2 and 2,3-dinor-TXB2 in humans and rats. We report on the excretion of 2,3-dinor-TXB2 in the rat. This novel approach to the extraction of urinary thromboxanes is more convenient than currently available methods in terms of simplicity, rapidity, and recovery. This method could be extended to any other prostanoid for which an antibody could be obtained.

Animals↗
PubMed1987

Prostaglandin and thromboxane synthesis by M5076 ovarian reticulosarcoma during growth: effects of a thromboxane synthetase inhibitor.

The five stable metabolites [prostaglandin F2 alpha (PGF2 alpha), prostaglandin D2 (PGD2), prostaglandin E2 (PGE2), thromboxane B2 (TXB2), and 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha)] of arachidonic acid (AA) via the cyclooxygenase pathway were measured by high-resolution gas chromatography-mass spectrometry in M5076 ovarian reticulosarcoma (M5) homogenates at various times after tumor implantation (Days 15, 18, 21, and 24). Vegetating tumor showed an active AA overall metabolism, which significantly increased during tumor growth. Synthesis of selected products (TXB2, PGD2, and PGE2) increased markedly over time (up to 10.6, 3.5, and 0.9 micrograms/g, respectively). The overall metabolic profile was TXB2 much greater than PGD2 greater than PGF2 alpha greater than 6-keto-PGF1 alpha greater than PGE2 on Day 15 and TXB2 much greater than PGD2 much greater than PGF2 alpha greater than 6-keto-PGF1 alpha on Day 24. TXB2 was also by far the most abundant product of in vitro-cultured M5 cells. Chronic treatment of M5-bearing mice with dazmegrel (UK-38,485), a selective thromboxane synthetase inhibitor (100 mg/kg p.o. daily, from Day 7 to killing), resulted in incomplete TXB2 synthesis inhibition, AA metabolism diversion toward the other prostaglandins, and no effects of tumor growth and metastasis. More frequent dazmegrel treatment (100 mg/kg p.o. every 8 h from Day 1 to killing) resulted in complete TXB2 synthetase inhibition, AA metabolism diversion, and increased tumor growth and metastasis. These data do not support the hypothesis of thromboxane synthetase inhibitors reducing tumor growth. However, since TXB2 suppression was accompanied by the production of other products possibly interfering in tumor growth, no conclusions on the effective role of TXA2 in malignancy can be drawn.

Animals↗
PubMed1987

Arachidonic acid metabolic profiles in human meningiomas and gliomas.

We determined arachidonic acid (AA) cyclooxygenase metabolic profiles in specimens of human intracranial tumors (gliomas and meningiomas) and, when available, normal brain tissue. Samples were collected at surgery and immediately frozen in liquid nitrogen. The five stable metabolites of AA (PGE2, PGD2, PGF2 alpha, 6-keto-PGF1 alpha and TXB2) were measured by high-resolution gas chromatography-mass spectrometry after ex vivo metabolism of endogenous AA by tissue homogenates. The absolute amounts of AA metabolites varied widely between samples, though meningiomas and gliomas showed characteristic profiles. Compared to the slow-growing benign meningiomas, the rapidly-growing infiltrating gliomas had higher synthesis of TXA2 (reported as a procancer metabolite) and lower synthesis of PGD2 and PGI2 (reported as anticancer metabolites). A higher overall synthesis capacity, preferentially toward TXA2, was found in glioblastomas than in non-pathological brain tissue.

Arachidonic Acid↗
PubMed1987

Effect of butylated hydroxyanisole on in vitro and in vivo nitrosation of dibutylamine.

The effect of the food additive butylated hydroxyanisole on the nitrosation of dibutylamine was studied in vitro and in vivo, in rats. At the highest concentration tested, butylated hydroxyanisole significantly inhibited the in vitro formation of N-nitrosodi-n-butylamine from dibutylamine and nitrite by 35%. This effect was not observed in animals given dibutylamine, NaNO2 and butylated hydroxyanisole by gavage in the same ratio that produced an effect in vitro. The oral administration of butylated hydroxyanisole to rats given 0.5% nitrate in the drinking water and dibutylamine (0.38 mmol/kg 3 times/day p.o.) was also with no effect, although the experimental model used proved suitable for studying the modulating effect on endogenous nitrosation of different chemicals such as ascorbic acid or potassium thiocyanate. The discrepancy between in vitro and in vivo results is discussed.

Animals↗
PubMed1987

[Release of beta-endorphin and beta-lipotropin during submaximal exertion in sedentary and active subjects. Endogenous opiate peptides during exertion in sedentary and active subjects].

Some recent studies suggest that changes in the endogenous opioid peptides (POE) secretion during stress may be involved in various hemodynamic, respiratory and hormonal responses to exercise. To evaluate the relationship between fitness and POE release, 10 mixed-type exercise trained athletes (A) and 10 sedentary normal controls (C) were examined by bicycle stress testing; maximum oxygen uptake (VO2max) and peak work load (PWL) were greater in A than C (VO2max = 61.8 +/- 5.2 vs 40.2 +/- 6.1 ml/kg; PWL = 1525 +/- 229 vs 915 +/- 305 kgm.both p less than 0.01). After 24 hours A and C underwent rectangular bicycle stress testing (two 20' steps at 60% and 80% VO2max). Total plasmatic beta-endorphin (BEP) and its precursor beta-lipotropin (BLPH) were dosed by radioimmunoassay at rest, at 60% VO2max, at 80% VO2max and after complete recovery. Physical exercise caused a transient rise of BEP + BLPH plasma levels in both A and C. In A the increase was greater and occurred earlier than in C. The POE release under submaximal exercise showed a close correlation with oxygen uptake and therefore with fitness. This relation appeared in A at both low and high effort levels, whereas in C it was more strict at higher effort level. There results suggest that POE system play an important role in the adaptive mechanisms in sport practice.

Adult↗
PubMed1987

Experimental model for investigating bladder carcinogen metabolism using the isolated rat urinary bladder.

The capacity of the isolated rat urinary bladder to metabolize chemical carcinogens was studied. Under our experimental conditions, the bladder carcinogen N-nitrosobutyl-(4-hydroxybutyl)amine (NBHBA) was oxidized to N-nitrosobutyl(3-carboxypropyl)amine (NBCPA). A time-dependent increase in the amount of NBCPA formed and a simultaneous disappearance of NBHBA indicated that the bladder can metabolize NBHBA to the metabolite considered to be responsible for tumour induction in the urinary bladder of laboratory animals. After 15, 30, 60 and 120 min, the percentages of NBCPA formed were 10%, 21%, 35% and 61%, respectively, and 59%, 49%, 36% and 25% of NBHBA remained unchanged. When N-nitrosodi-n-butylamine (NDBA) was introduced into the isolated urinary bladder and incubated for 120 min, its oxidized metabolites NBHBA and NBCPA were formed, in amounts of 0.13% and 0.06% of the substrate added.

Animals↗
PubMed1987

Effect of butylated hydroxyanisole on the metabolism of N-nitrosodi-n-butylamine and N-nitrosobutyl(4-hydroxybutyl)amine by rat hepatic S9 preparations in vitro.

N-Nitrosodi-n-butylamine (NDBA), the NADPH generating system and various concentrations of butylated hydroxyanisole (BHA) added to rat hepatic S9 fractions resulted in a significant drop (30-50%) in N-nitrosobutyl(4-hydroxybutyl)amine (NBHBA) formation and a consequent rise in the amount of substrate recovered unchanged. When NBHBA and NAD+ were incubated with BHA and S9 fractions, the amount of N-nitrosobutyl(3-carboxypropyl)amine (NBCPA) was decreased by 20-40%, and the amount of unmetabolized NBHBA increased.

Animals↗
PubMed1987

Beta-oxidation of N-nitrosodiethanolamine in different animal species in vitro and in vivo.

The metabolism of N-nitrosodiethanolamine (NDELA) was studied to assess whether the formation of the beta-oxidized metabolites, N-nitroso(2-hydroxyethyl) (formylmethyl)amine (NHEFMA) and N-nitroso(2-hydroxyethyl)(carboxymethyl)amine (NHECMA), is involved in tumour induction in various animal species with different susceptibilities to NDELA carcinogenicity. In-vitro and in-vivo studies showed that all the animal species considered metabolize NDELA through the beta-oxidation pathway, suggesting that there is no correlation between carcinogenesis by NDELA and its beta-oxidation.

Animals↗
PubMed1986

Serum methanol concentrations in rats and in men after a single dose of aspartame.

Serum methanol concentrations were measured in rats and in humans given oral aspartame. The dose given to rats was the FDA's projected 99th percentile daily intake for humans, assuming aspartame were to replace all sucrose sweeteners in the diet (34 mg/kg). Four male adult volunteers each received 500 mg, equivalent to 6-8.7 mg/kg, which is approximately the FDA's estimate of mean daily human consumption. Both treatments caused a rise in serum methanol. In rats the mean peak value was 3.1 mg/litre 1 hr after administration; serum methanol returned to endogenous values 4 hr after treatment. In the men, the mean rise over endogenous values was 1.06 mg/litre after 45 min. Two hours after treatment, serum methanol had returned to basal levels. The temporary serum methanol increase showed peak values within the range of individual basal levels.

Adult↗
PubMed1986

Comparative in vitro and in vivo beta-oxidation of N-nitrosodiethanolamine in different animal species.

The metabolism of N-nitrosodiethanolamine (NDELA) was studied to assess whether the formation of the beta-oxidated metabolites N-(2-hydroxyethyl)-N-(formylmethyl)nitrosamine (EFMN) and N-(2-hydroxyethyl)-N-(carboxymethyl)nitrosamine (ECMN) is involved in the mechanism of tumor induction in various animal species with different susceptibility to NDELA carcinogenicity. In vitro studies using liver S9 fractions from rats, hamster, B6C3F1 and CD-1 mice and rabbits showed that all the animal species metabolize NDELA through the beta-oxidation pathway, although to different extents. Urinary excretion of NDELA and its metabolite ECMN in rats, hamsters and mice after 5 mg X kg-1 NDELA i.p. confirmed these findings. The results suggest there is no correlation between carcinogenesis by NDELA and its beta-oxidation. The possibility that ECMN formation might represent a detoxifying metabolic pathway for NDELA is discussed.

Alcohol Dehydrogenase↗
PubMed1986

Trace analysis of methanol in rat serum by headspace high resolution gas chromatography/selected ion monitoring.

A high resolution headspace gas chromatography/selected ion monitoring analytical method has been developed for the quantitation of methanol in body fluids. The addition of tetradeuterated methanol as internal standard gives this method high accuracy and reproducibility. The high sensitivity of the mass spectrometer permits analysis of methanol in aqueous solutions at concentrations down to 0.012 mg/l. The analytical procedure described was used to measure serum methanol in rats given 5 mg/kg of this alcohol orally. The method proved suitable for analysis of endogenous levels of methanol and of variations close to endogenous levels.

Animals↗