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P Millburn

Publications and source records attributed to P Millburn.

At least 19 recordsLinked to original sources
PubMed1987

The toxicity and metabolism of the pyrethroids cis- and trans-cypermethrin in rainbow trout, Salmo gairdneri.

1. The toxicity of cis- and trans-cypermethrin to rainbow trout was investigated and the concentrations of the two isomers in brain associated with toxic signs (excitability and loss of equilibrium) were determined. cis-Cypermethrin and trans-cypermethrin were equally toxic and showed similar brain levels associated with toxic signs (cis:0.25 micrograms/g, mean (range 0.07-0.53); trans:0.17 micrograms/g (0.07-0.31]. 2. Orally administered cypermethrin was less toxic than predicted, probably due to poor intestinal uptake. Toxicity was due to absorption via the gills of unchanged pyrethroid excreted from the intestine into the water. 3. The metabolism of the radiolabelled insecticides, [14C-cyclopropyl]- and [14C-benzyl]-cis- and trans-cypermethrin has been investigated in vivo and in vitro. 4. The principal route of elimination in vivo was the bile, with 20-28% dose excreted as biliary metabolites in 24 h. No difference in the rates of elimination of the cis and trans isomers was observed. 5. cis-Cypermethrin was metabolized primarily to the glucuronide of 4'-hydroxy-cypermethrin (80% total bile radioactivity), together with dichlorovinyldimethylcyclopropanecarboxylic acid and its glucuronide, 3-(4-hydroxyphenoxy)benzoic acid (4'-hydroxy-3BPA) and its ester and ether glucuronides, 3-phenoxybenzoyl glucuronide and 4'-hydroxy-3BPA sulphate were detected. trans-Cypermethrin was metabolized to the same products, but with only 36% as 4'-hydroxy-cypermethrin glucuronide.

Animals↗
PubMed1986

Comparative toxicity of cis-cypermethrin in rainbow trout, frog, mouse, and quail.

The synthetic alpha-cyano-phenoxybenzyl-containing pyrethroid insecticides act on the CNS of vertebrates and show a species-selective toxicity in the order fish greater than amphibians much greater than mammals greater than birds. Concentrations of [14C]cis-cypermethrin in the brains of representative members of each of these classes of chordates were measured at toxic signs (an onset of hyperactivity followed by seizures and loss of balance/equilibrium) as an indicator of target organ sensitivity. The concentration of cis-cypermethrin in brain, associated with toxic signs, in micrograms per gram (mean +/- SE) as determined by high-performance liquid chromatography was 0.08 +/- 0.03 (frog), 0.23 +/- 0.05 (trout), 1.71 +/- 0.33 (mouse), and 3.94 +/- 0.88 (quail). Trout brain was equally sensitive to the cis and trans isomers of cypermethrin. In both mouse and quail, some 90% of the radioactivity in the brain was parent pyrethroid. Trout and frog, however, afforded only 56 and 32%, respectively, of the brain 14C as cypermethrin, with the remaining radioactivity in both extractable and nonextractable metabolites, including 4'-hydroxy-cis-cypermethrin, which is potentially neuroactive. Following oral administration, cis-cypermethrin was readily absorbed and metabolized by quail. Intestinal uptake was far less rapid in trout and mouse, with unchanged cypermethrin dispersed in secreted bile, being readily eliminated from the intestines of fish. The uptake and metabolism of cis-cypermethrin and the brain sensitivities of these animals to the pyrethroid account for the observed differences in acute toxicity.

Animals↗
PubMed1986

Reactive intermediates from 3-hydroxybenzo[a]pyrene and its glucuronide.

3-Hydroxybenzo[a]pyrene (3-OH-BaP) is oxidized by the horseradish peroxidase/H2O2 system to benzo[a]pyrene-3,6-quinone. In the presence of N-acetylcysteine one other product is also formed. This was identified by its chemical, and u.v., mass and n.m.r. spectral properties as 6-(H-acetyl-cystein-S-yl)-3-hydroxybenzo[a]pyrene (6-NAc-cys-3-OH-BaP). Replacement of the N-acetylcysteine by glutathione leads to the formation of a 3-OH-BaP-glutathione adduct. Enzymic hydrolysis of benzo[a]pyrene-3-glucuronide in the presence of N-acetylcysteine yields, in addition to 3-OH-BaP, a product which co-chromatographs with 6-NAc-cys-3-OH-BaP and has identical chemical and spectral characteristics.

Acetylcysteine↗
PubMed1985

Secondary metabolites of benzo[a]pyrene: 3-hydroxy-trans-7,8-dihydro-7,8-dihydroxybenzo[a]pyrene, a biliary metabolite of 3-hydroxybenzo[a]pyrene in the rat.

Rats administered 3-hydroxybenzo[a]pyrene (50 mg/kg, i.p.), excrete via the bile metabolites which, after treatment with beta-glucuronidase and aryl sulphatase, yield, in addition to 3-hydroxybenzo[a]pyrene, 3-hydroxy-trans-7,8-dihydro-7,8-dihydroxybenzo[a]pyrene (3-OH-BP-7,8-diol) and a minor, highly labile, metabolite tentatively identified as 3,5-dihydroxybenzo[a]pyrene. These novel metabolites are readily isolated in a pure state via preparative layer chromatography. The structure of the 3-OH-BP-7,8-diol was revealed by its u.v., proton magnetic resonance and mass spectral properties. Its hydroxyl functions are in a predominantly quasi-diequatorial conformation.

Animals↗
PubMed1985

Metabolism and enterohepatic circulation of benzo(a)pyrene-4,5-epoxide in the rat.

After i.v. administration of 3H-benzo(a)pyrene-4,5-epoxide (32.5 mumol/kg) to rats, 76% of the 3H appeared in bile within 3 h. The glutathione conjugate of benzo(a)pyrene-4,5-epoxide was the major biliary metabolite (33% of dose), together with a glucuronic acid conjugate of benzo(a)pyrene-4,5-diol (18%) and an unidentified metabolite (10%). The glutathione and glucuronic acid conjugates both undergo extensive enterohepatic circulation. Thus, following the intraduodenal administration of the 3H-labelled conjugates, 26% of the radioactivity was excreted in the bile after 24 h in the case of the glutathione derivative, and 40% in the case of the glucuronide. The benzo(a)pyrene-4,5-diol glucuronide, on enterohepatic circulation, appears in the bile in the same form as the conjugate administered with no evidence of further metabolism of the polycyclic hydrocarbon moiety. The glutathione conjugate of benzo(a)pyrene-4,5-epoxide, on recirculation, is reexcreted in bile as one unidentified metabolite, which is susceptible to the action of arylsulphatase.

Animals↗
PubMed1983

Mutagenicity and in vivo disposition of biliary metabolites of benzo(a)pyrene.

Rabbits and rats administered [3H]benzo(a)pyrene (BP; 40 mumol/kg, i.v.) excreted, via the bile, metabolites which increased reverse gene mutation frequency in Salmonella typhimurium TA98 when incubated with beta-glucuronidase. Glucuronic acid conjugates of BP 4,5-diol, BP 1,6-, 3,6- and 6,12-quinones were detected in rat bile with low levels of 3- and 9-OH BP and BP 7,8- and 9,10-diols. In rabbits BP 9,10-diol was the major aglycone along with smaller amounts of BP 1,6- and 3,6-quinones, BP 4,5- and 7,8-diols and 3- and 9-OH BP. Qualitatively similar metabolic profiles were found when animals were given 3 mumol/kg [3H]BP. When 3H-labelled biliary metabolites, which contained the mutagenic component, were administered intraduodenally to rats, radioactivity reached the systemic circulation but DNA adducts were not detectable (less than 0.03 pmol/mg DNA) in tissues (intestinal wall, liver and lung) exposed to the reabsorbed metabolites.

Animals↗
PubMed1982

Metabolism and excretion of benzo[a]pyrene in the rabbit.

1. Following i.v. administration of [14C]benzo[a]pyrene (3 mumol/kg) to rabbits, 30% of the 14C dose appeared in bile and 12% in urine, within six hours. 2. Biliary and urinary metabolites were mainly conjugated; less than 12% of the 14C was extractable with ethyl acetate, but after treatment with beta-glucuronidase or aryl sulphatase 30-40% became extractable. 3. H.p.l.c. analysis of the extracts indicated that the major non-polar metabolite was benzo[a]pyrene, 9,10-diol (18% of 14C in bile and 24% of 14C in urine, mainly conjugated with glucuronic acid). Smaller amounts of the 4,5-diol, the 3,6-quinone, and the 9-hydroxy- and 3-hydroxybenzo[a]pyrene were also found in bile (total less than 10%), together with 9-hydroxybenzo[a]pyrene and two unknown metabolites (X and Y) in urine (total less than 4%). 4. The proximate carcinogen, the 7,8-diol, was not detected in any extract. 5. After intraduodenal administration of biliary metabolites of [14C]benzo[a]pyrene (approx. 0 X 3 mumol), 14C was excreted in the bile (21% dose) and urine (14%) within 23 h, indicating that metabolites can undergo enterohepatic circulation in the rabbit.

Animals↗
PubMed1981

Biliary excretion, systemic availability and reactivity of metabolites following intraportal infusion of [3H]benzo[a]pyrene in the rat.

Following the intraportal infusion of [3H]benzo[a]pyrene (BP) at two dose levels (5 and 0.125 mumol/kg) in the rat, metabolites were excreted via the bile and were released into the hepatic venous blood. At each dose level, a significant portion (approx. 15-18%) of biliary metabolites was directly extractable with ethyl acetate and a total of approx. 24-32% became extractable after incubation of bile with beta-glucuronidase. More than 65% and 70% of the 3H in blood and liver, respectively, was directly extractable with ethyl acetate. The h.p.l.c. profile of extracted metabolites was found to differ at the two dose levels studied. The binding of reactive metabolites to hepatic protein and DNa was measured at four dose levels of [3H]BP. The possible availability of hepatic-derived metabolites to extra-hepatic sites is discussed.

Animals↗
PubMed1981

Species variations in the renal and hepatic conjugation of 3-phenoxybenzoic acid with glycine.

1. 3-Phenoxy[14C]benzoyl-CoA has been chemically synthesized, purified and characterized by field-desorption mass spectrometry. Biological activity of the purified thioester was greater than 92%. 2. The two enzymic steps involved in the conjugation of 3-phenoxybenzoic acid (3PBA) with glycine have been investigated in hepatic and renal tissues from various mammalian species. 3. A 10- to 300-fold excess of acyl-CoA: glycine N-acyltransferase activity as compared with acyl-CoA synthetase activity was found in most tissue preparations, while the rate of the activating step matched that of the overall process. This suggests that formation of the acyl-CoA thioester (3PBA-CoA) is the rate-limiting step in the conjugation of 3PBA with glycine. 4. In most of the species tested, renal activities were higher than those of corresponding liver preparations. 5. The gerbil and ferret, which excrete 3-phenoxybenzoylglycine as the principal urinary metabolite of 3PBA, gave the highest 3PBA-CoA synthetase and glycine N-acyltransferase activities in vitro. By contrast, the hamster, which excretes only small amounts of the glycine conjugate of 3PBA, had the lowest enzymic activities in vitro. 6. In the mouse and rat there were differences between the patterns of metabolism found in vivo and in vitro, and possible reasons for this are discussed.

Acetate-CoA Ligase↗
PubMed1980

Enterohepatic recycling of phenolphthalein, morphine, lysergic acid diethylamide (LSD) and diphenylacetic acid in the rat. Hydrolysis of glucuronic acid conjugates in the gut lumen.

1. Biliary elimination in female Wistar albino rats 3 h after i.p. injection of [3H]phenolphthalein, [3H]morphine, 14C-LSD and [14C]diphenylacetic acid was 90%, 45%, 75% and 57% respectively, predominantly as glucuronides. 2. Infusion of 3 h bile from the previous experiments into the duodena of bile-duct-cannulated animals demonstrated enterohepatic circulation, amounting in 24 h to 85%, 41%, 28% and 66% of the infused doses of the conjugates of phenolphthalein, morphine, LSD and diphenylacetic acid respectively. 3. Pretreatment with antibiotics to suppress intestinal microflora decreased this enterohepatic recirculation to 22%, 8.6% and 21% in 24 h for phenolphthalein, morphine and diphenylacetic acid glucuronides respectively. Antibiotic pretreatment did not influence the absorption and re-excretion of infused doses of the free aglycones, thus demonstrating the importance of bacterial beta-glucuronidase hydrolysis of the biliary conjugates. 4. The extent of intestinal absorption of the aglycones after bacterial beta-glucuronidase hydrolysis of the conjugates is related to their lipid-solubility as estimated by octan-1-ol:0.1 M phosphate buffer partition ratios (P-values). 5. The persistence of compounds in the enterohepatic circulation is determined by the faecal and urinary elimination of the circulating compounds. Faecal elimination is governed by the extent of intestinal absorption of the circulating compounds, which is influenced by the efficacy of intestinal hydrolysis of the conjugates and the relative lipophilicity of the aglycones released.

Animals↗
PubMed1978

Taurine conjugates as metabolites of arylacetic acids in the ferret.

1. The pattern of conjugation in the ferret of 8 arylacetic acids and, for comparison, benzoic acid and 4-nitrobenzoic acid was examined. 2. The arylacetic acids, phenylacetic, 4-chloro- and 4-nitro phenylacetic, alpha-methylphenylacetic (hydratropic), 1- and 2-naphthylacetic and indol-3-ylacetic acids, were excreted in the urine as taurine and glycine conjugates. Diphenylacetic acid did not form an amino acid conjugate and was excreted as a glucuronide. 3. The taurine conjugate was the major metabolite of 4-nitrophenylacetic, alpha-methylphenylacetic, 1- and 2-naphthylacetic and indol-3-ylacetic acids, whereas the glycine conjugate was the major metabolite of phenylacetic and 4-chlorophenylacetic acids. Taurine conjugation did not occur with benzoic and 4-nitrobenzoic acids which were excreted as glycine and glucuronic acid conjugates. 4. Phenacetylglutamine and 4-hydroxyphenylacetic acid were minor urinary metabolites of phenylacetic in the ferret. 5. A number of taurine conjugates of aliphatic and aromatic acids were synthesized and their characterization and properties were studied. The role of taurine as an alternative to glycine in the metabolic conjugation of arylacetic acids is discussed.

Acetates↗
PubMed1978

The influence of dose on the pattern of conjugation of phenol and 1-naphthol in non-human primates.

1. The pattern of conjugation of phenol and 1-naphthol was investigated in several primates; three Old World species (rhesus, cynomolgus, patas monkeys), two New World species (capuchin, tamarin), and two prosimians (bushbaby, tree shrew). 2. Following intra-muscular phenol or 1-naphthol (10 mg/kg), sulphation was the major conjugation in the Old World monkeys and prosimians, whereas glucuronidation predominated in the New World species. 3. In rhesus and cynomolgus monkeys, sulphation decreased as dose increased, but remained the major conjugation with both substrates at dose levels of 0.01 to 25 mg/kg. 4. In the capuchin, the conjugation pattern of phenol changed markedly as dose increased; at 0.01 and 1 mg/kg sulphation was the major conjugation, whereas at 10 and 25 mg/kg glucuronidation predominated. With 1-naphthol only small amounts of sulphate were excreted; glucuronic acid conjugation was the major metabolism at all four dose levels. 5. The importance of considering both substrate and dose when making inter-species comparisons, particularly with man, is discussed.

Animals↗