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At least 19 recordsLinked to original sources
PubMed1998

Mechanistic study on liver tumor promoting effects of piperonyl butoxide in rats.

Piperonyl butoxide, alpha-[2-(2-butoxyethoxy)ethoxy]-4,5-methylenedioxy-2-propyltol uene, is a widely used pesticide-synergist. Recently, results were reported indicating that piperonyl butoxide is a hepatocarcinogen in rat. Since the underlying mechanism was not elucidated, we examined the effects on rat liver cells in detail. For this purpose male F344 rats were administered piperonyl butoxide mixed in the diet at concentrations of 0 (negative control), 0.05, 0.2 or 2% for 2 days, 1, 2, and 4 weeks. As a positive control, phenobarbital was administered to rats for up to 4 weeks as a 0.1% solution in the drinking water. Increased liver weight, centrilobular hepatocellular hypertrophy due to increased smooth endoplasmic reticulum, decreased numbers and areas of connexin 32-positive spots per hepatocyte, and increased cell proliferation were observed in rats treated with 0.2 and 2% piperonyl butoxide. Similar results were obtained for 0.1% phenobarbital treated rats. Hepatocellular necrosis suggestive of hepatotoxicity was also observed in the 2% piperonyl butoxide group. These results indicate that the promoting mechanism of piperonyl butoxide in hepatocarcinogenesis is similar to that of phenobarbital, involving an ability to induce CYP isoenzymes and inhibit gap junctional intercellular communication. In addition, increased cell proliferation following hepatocellular necrosis may also play a role at high doses.

Animals↗
PubMed1984

Anticonvulsant activity and neurotoxicity of piperonyl butoxide in mice.

Piperonyl butoxide, a microsomal monooxygenase inhibitor, administered intraperitoneally to mice exerts peak anti-maximal electroshock activity and peak neurotoxicity at 5 and 7h, respectively. The median neurotoxic dose is 1,690 mg/kg. In the maximal electroshock seizure test, the median effective dose (ED50) is 457 mg/kg and the protective index (PI) is 3.69. In the subcutaneous pentylenetetrazol test, the ED50 is 443 mg/kg and the PI is 3.81. Piperonyl butoxide prevents seizure spread and elevates seizure threshold. Its PI compares favorably with PIs of clinically useful anticonvulsants.

Animals↗
PubMed1984

Changes of hexachlorobutadiene nephrotoxicity after piperonyl butoxide treatment.

The effects of piperonyl butoxide on hexachlorobutadiene (HCBD) nephrotoxicity were measured. The time course and severity of toxicity were affected. Five hours after either piperonyl butoxide or HCBD glomerular filtration rate (GFR) was decreased; at 24 h GFR had recovered for the piperonyl butoxide group but continued to fall in the HCBD group. The group treated with piperonyl butoxide and HCBD had the same GFR as the group treated with just HCBD. At 24 h after HCBD the piperonyl butoxide pretreated group was not different from the oil pretreated controls. At 48 h after HCBD, reabsorbtion of water and glucose was more severely impaired in the group pretreated with piperonyl butoxide. These results support the hypothesis that HCBD metabolites are involved in renal tubular dysfunction.

Animals↗
PubMed1996

Lack of genotoxicity of piperonyl butoxide.

The genotoxicity of piperonyl butoxide has been investigated in bacterial mutation assays using tester strains TA98, TA100, TA1535, TA1537 and TA1538. The assays were conducted both with and without metabolic activation. Piperonyl butoxide was tested for mutation with and without metabolic activation in the CHO/HGPRT assay. Chromosomal aberrations were investigated also using Chinese hamster ovary (CHO) cells and effects on DNA were evaluated by in vitro unscheduled DNA synthesis (UDS) test using rat liver primary cell cultures. Piperonyl butoxide was not shown to be genotoxic in any assay system. The data presented supports the view that the liver tumors observed in rodents at dose levels above the maximally tolerated dose (MTD) result from a secondary non-genotoxic mechanism.

Animals↗
PubMed1993

Subacute toxicity of piperonyl butoxide in ICR mice.

Piperonyl butoxide, alpha-[2-(2-butoxyethoxy)ethoxy]-4,5-methylenedioxy-2-propyltol uene, is a pesticide synergist. ICR mice of both sexes were maintained on diet containing 0, 0.1, 0.3 or 0.9% of piperonyl butoxide for 20 days. At the end of the experimental period, they were necropsied. Selected organs were weighed and serum chemistries were analyzed. In male and female mice of the 0.9% group, body weight, kidney and spleen weight were depressed in comparison to those of control group. Liver weight of the 0.3 and 0.9% group of both sexes were significantly higher than those of control group. Mice of the 0.9% group of both sexes had increased serum levels of cholesterol, total protein, gamma-glutamyl transpeptidase. Histological examination of livers from mice of the 0.9% group by light microscopy showed enlarged hepatocytes, anisonucleosis and single cell necrosis. The results indicated that subacute toxicity of piperonyl butoxide in ICR mice was directed primarily at liver.

Animals↗
PubMed1992

Sub-acute toxicity of piperonyl butoxide in F344 rats.

Piperonyl butoxide, alpha-[2-(2-Butoxyethoxy)ethoxy]-4,5-methylenedioxy- 2-propyltoluene, is a pesticide synergist. F344 rats of both sex were maintained on diets containing 0, 0.6, 1.2 or 2.4% of piperonyl butoxide for 13 weeks. At the end of experimental period, they were necropsied. Selected organs were weighted and serum was analyzed by clinical chemistry. In male and female rats of the 2.4%-group, body weight gains were depressed, macroscopically, hepatomegaly was marked and liver weights were significantly higher than those of the control group. In male and female rats of all treated groups, relative kidney weights were significantly increased in a dose-dependent manner. Rats of the 2.4%-group had increased levels of albumin, cholesterol, urea nitrogen and gamma-glutamyl transpeptidase. Examination of livers of the male 2.4%-group by light microscopy showed enlarged hepatocytes with glassy cytoplasm and fatty deposition. On occasion, there was coagulative necrosis of a few hepatocytes in the periportal area and oval cell proliferation. The kidney of treated rats showed atrophy of epithelium in the proximal convoluted tubules. These results indicated that toxicity of piperonyl butoxide in rats was directed primarily to the liver and kidney.

Animals↗
PubMed1993

Behavioural effects of piperonyl butoxide in male mice.

Piperonyl butoxide was administered to male mice from 5 to 12 weeks of age in the diet at levels of 0 (control), 0.15, 0.30, and 0.60%, and some behavioural parameters were measured. The animals performed three trials in multiple water T-maze at 10 weeks of age, and the number of errors was significantly decreased in treatment groups on the 3rd trial, while there was no biologically significant effect of piperonyl butoxide on maze learning. The motor activity of the exploratory behaviour was measured by ANIMATE AT-420 at 8 and 11 weeks of age. At 8 weeks of age, some parameters were increased in the 0.30% group, while there was no consistent compound- or dose-related effect. At 11 weeks of age, some parameters were different in treatment groups, and there were biologically consistent significant effects; i.e., number of movements, movement time, total distance, average speed, and number of turnings increased. From these results, piperonyl butoxide showed adverse effects on the motor activity of the exploratory behaviour in male mice.

Animals↗
PubMedDate not supplied

Developmental toxicity study of piperonyl butoxide in CD rats.

Piperonyl butoxide was administered to pregnant rats by gavage at a level of 0 (control), 630, 1065, and 1800 mg/kg bw on days 11-12 of gestation. The animals were killed on day 20 of gestation. Average maternal body weight gain (gestational days 11-20) was significantly reduced in the 1065 and 1800 mg/kg bw groups. Total resorption rate was significantly increased in the 1800 mg/kg bw group and those effects were significantly dose-related. The average fetal body weight of each sex was significantly reduced in the 1065 and 1800 mg/kg bw groups. External limb deformity (oligodactyly, syndactyly, and polydactyly) was significantly increased in the 1065 and 1800 mg/kg bw groups in a dose-related manner. The dose levels of piperonyl butoxide in the present study produced limb deformities in rats.

Animals↗
PubMed1994

Developmental toxicity evaluation of piperonyl butoxide in CD-1 mice.

Piperonyl butoxide was administered to pregnant mice by gavage at a level of 0 (control), 1065, 1385 and 1800 mg/kg body weight only on day 9 of gestation. The animals were sacrificed on day 18 of gestation. Early and late foetal deaths were significantly increased in the higher dose groups and those effects were significantly dose-related. The average body weights of male and female foetuses were significantly reduced in a dose-related fashion. The external malformation of oligodactyly in forelimbs was significantly increased in higher treatment groups in a dose-related manner. The dose levels of piperonyl butoxide in the present study produced adverse effects on developmental parameters.

Abnormalities, Drug-Induced↗
PubMed1994

Human in vivo percutaneous absorption of pyrethrin and piperonyl butoxide.

In order to determine the human in vivo percutaneous absorption of pyrethrin and piperonyl butoxide, a commercial formulation containing either [14C]pyrethrin (3.8 mCi/mmol) or [14C]piperonyl butoxide (3.4 mCi/mmol) was applied to the ventral forearm of six human volunteers. The formulation contained 0.3% pyrethrin and 3.0% piperonyl butoxide. Spreadability studies showed that concentrations of 5.5 micrograms pyrethrin/cm2 and 75.8 micrograms piperonyl butoxide/cm2 (used in this study) would be consistent with levels found in actual use. The forearms were thoroughly cleansed with soap and water 30 min after application (as recommended for actual use). Percutaneous absorption was determined by urinary cumulative excretion following dose application. With a 7-day urinary accumulation, 1.9 +/- 1.2% (SD) of the dose of pyrethrin and 2.1 +/- 0.6% of the dose of piperonyl butoxide applied was absorbed through the forearm skin. 1 hr after application blood samples contained no detectable radioactivity. The percutaneous absorption of pyrethrin and piperonyl butoxide from the scalp was calculated to be 7.5% of the applied dose for pyrethrin and 8.3% for piperonyl butoxide. The calculated half-life of 14C excretion was 50 hr for pyrethrin and 32 hr for piperonyl butoxide. The data should be of relevance to appropriate risk assessment in extrapolating animal data to humans.

Administration, Cutaneous↗
PubMed1996

Interaction between fenbendazole and piperonyl butoxide: pharmacokinetic and pharmacodynamic implications.

The effect of the cytochrome P450 inhibitor, piperonyl butoxide on the pharmacokinetics and anthelmintic efficacy of the benzimidazole compound fenbendazole was studied in sheep and goats. Pretreatment of goats with the inhibitor caused a greater than three-fold increase in the relative bioavailability of fenbendazole and fenbendazole sulphoxide. A pharmacokinetic dose titration study was carried out in sheep with fenbendazole (5 mg kg-1) and piperonyl butoxide administered orally at 0, 15, 31, 63, 125 and 250 mg kg-1. The AUC of fenbendazole and the sulphoxide were significantly increased when fenbendazole was co-administered with piperonyl butoxide at dose rates equal to or higher than 31 mg kg-1. Peak plasma concentrations (Cmax) and mean residence time (MRT) were also significantly increased. The efficacy of the combination was assessed in sheep against two species of benzimidazole-resistant abomasal nematodes; Ostertagia circumcincta and Haemonchus contortus. The percentage reduction in the total number of O. circumcincta worms was 7.9% (fenbendazole) and 97.8% (fenbendazole-piperonyl butoxide). For H. contortus, the percentage reduction was 84.8% (fenbendazole) and 99.0% (fenbendazole-piperonyl butoxide). The in-vitro S-oxidation of fenbendazole and fenbendazole sulphoxide was studied using microsomal preparations from rat liver. Piperonyl butoxide inhibited significantly the sulphoxidation and sulphonation of fenbendazole. It was concluded that piperonyl butoxide inhibited the oxidative conversion of fenbendazole into inactive metabolites and this resulted in a potentiated anthelmintic action.

Animals↗
PubMed1992

Reproductive and neurobehavioural effects in three-generation toxicity study of piperonyl butoxide administered to mice.

Piperonyl butoxide (PB) was administered continuously to mice from 5 weeks of age in the F0 generation to weaning of the F2 generation. PB was administered in the diet at levels of 0 (control), 0.1, 0.2, 0.4 and 0.8%. Selected reproductive, developmental and behavioural parameters were measured. Litter size and litter weight were reduced in higher-dosed groups, and the body weight of the pups in the lactation period was reduced in dosed pups in each generation. The survival index at postnatal day 21 of the group receiving 0.8% PB was reduced in each generation. The developmental and behavioural parameters in the lactation period were little different from those of the controls, apart from olfactory orientation in the F1 generation. However, in the F2 generation mice, surface righting, cliff avoidance and olfactory orientation were adversely affected in treatment groups. The results suggest that PB had adverse effects on reproductive, developmental and behavioural parameters of mice, with increasing effects in subsequent generations of offspring.

Administration, Oral↗
PubMed1983

Effect of piperonyl butoxide on organic anion and cation transport in rabbit kidneys.

Piperonyl butoxide has been shown to reduce accumulation of cephaloridine in rabbit renal cortex; however, the mechanism responsible for this effect remains unclear. Cephaloridine is a zwitterion and its accumulation in renal cortex has been suggested to be regulated by both organic anion and cation transport systems. Thus, it was of interest to determine the effect of piperonyl butoxide on renal transport of p-aminohippurate (PAH, an organic anion) and tetraethylammonium (TEA, an organic cation). Although pretreatment with piperonyl butoxide markedly inhibited renal cortical uptake of cephaloridine, the same treatment had less inhibitory effect on either PAH or TEA uptake. Efflux of PAH from preloaded renal cortical slices was enhanced by pretreatment with piperonyl butoxide; however, TEA efflux was unaffected. Thus, piperonyl butoxide appears to have effects on renal membrane functions which result in differential effects on PAH, TEA, and cephaloridine transport.

Aminohippuric Acids↗
PubMed1977

Effect of piperonyl butoxide on disposition of di-2-ethylhexyl phthalate by rainbow trout.

1. Piperonyl butoxide in vitro inhibits the oxidation and hydrolysis of di-2-ethylhexyl phthalate, and the hydrolysis of the butyl ester of 2,4-dichloro-phenoxyacetic acid by liver homogenate fractions and serum from rainbow trout. 2. The rates of oxidation and hydrolysis of di-2-ethylhexyl phthalate by liver homogenates from rainbow trout pre-exposed to piperonyl butoxide (1 mg/l) were considerably lower than those by liver homogenates from control trout. 3. Disposition of di-2-ethylhexyl [14C]phthalate in rainbow trout in vivo was modified by pre-exposure to piperonyl butoxide. The piperonyl butoxide-treated trout had lower levels of 14C in bile and higher levels of 14C in blood and muscle than control trout. 4. Muscle of control and piperonyl butoxide-exposed trout showed similar concentrations of mono-2-ethylhexyl phthalate but the concentration of di-2-ethylhexyl phthalate in muscle from piperonyl butoxide-exposed trout was three times the control value.

Animals↗
PubMed1986

Uroporphyrin accumulation produced by halogenated biphenyls in chick-embryo hepatocytes. Reversal of the accumulation by piperonyl butoxide.

Cultures of chick-embryo hepatocytes were used to study the mechanism by which 3,4,3',4'-tetrachlorobiphenyl and 2,4,5,3',4'-pentabromobiphenyl cause accumulation of uroporphyrin. In a previous paper, an isoenzyme of cytochrome P-450 induced by 3-methylcholanthrene had been implicated in this process [Sinclair, Bement, Bonkovsky & Sinclair (1984) Biochem. J. 222, 737-748]. Cells treated with 3,4,3',4'-tetrachlorobiphenyl and 5-aminolaevulinate accumulated uroporphyrin and heptacarboxyporphyrin, whereas similarly treated cells accumulated protoporphyrin immediately after piperonyl butoxide was added. Piperonyl butoxide also restored haem synthesis as detected by incorporation of radioactive 5-aminolaevulinate into haem, and decrease in drug-induced 5-aminolaevulinate synthase activity. The restoration of synthesis of protoporphyrin and haem by piperonyl butoxide was not affected by addition of cycloheximide, indicating recovery was probably not due to protein synthesis de novo. Piperonyl butoxide also reversed uroporphyrin accumulation caused by 3,4,5,3',4',5'-hexachlorobiphenyl, mixtures of other halogenated biphenyls, lindane, parathion, nifedipine and verapamil. The effect of piperonyl butoxide was probably not due to inhibition of metabolism of these compounds, since the hexachlorobiphenyl was scarcely metabolized. Other methylenedioxyphenyl compounds, as well as ellipticine and acetylaminofluorene, also reversed the uroporphyrin accumulation caused by 3,4,3',4'-tetrachlorobiphenyl. SKF-525A (2-dimethylaminoethyl-2,2-diphenyl valerate) did not reverse the uroporphyrin accumulation caused by the halogenated biphenyls, but did reverse that caused by phenobarbital and propylisopropylacetamide. We conclude that the mechanism of the uroporphyrin accumulation cannot be due to covalent binding of activated metabolites of halogenated compounds to uroporphyrinogen decarboxylase.

2-Acetylaminofluorene↗
PubMed1996

Morphometric and immunohistochemical studies on atrophic changes in lympho-hematopoietic organs of rats treated with piperonyl butoxide or subjected to dietary restriction.

Changes observed in lympho-hematopoietic organs in rats given piperonyl butoxide may be attributable either to direct toxic effects or to undernutrition. Male F344 rats were therefore fed diet containing 2.5% piperonyl butoxide or subjected to a 64% restriction of food intake for 2 weeks. Marked inhibition of body weight gain, decreased white blood cell count, depletion of T/B lymphocytes in lymphoid tissues, hypoplasia of the bone marrow, and decreased proliferating cell nuclear antigen (PCNA) labeling indices in these tissues were seen in both dietary restriction and 2.5% piperonyl butoxide groups. The depletion of T lymphocytes in the thymus and spleen was stronger in the 2.5% piperonyl butoxide group, as indicated by PCNA labeling indices and image analysis of T lymphocyte areas of the spleen, however, the toxicological profile observed for the chemically treated group was essentially the same as for animals on the restricted diet. These results suggest that the lympho-hematopoietic findings in rats receiving 2.5% piperonyl butoxide are probably due to undernutrition resulting from a reduced food intake.

Animals↗
PubMed1980

The induction of hepatic cytochrome P-450 in C57 BL/10 and DBA/2 mice by isosafrole and piperonyl butoxide. A comparative study with other inducing agents.

The formation of cytochrome P-450 metabolite complexes with isosafrole and piperonyl butoxide in vivo in genetically 'responsive' C57 BL/10 mice and 'non-responsive' DBA/2 mice is described. Displacement of the isosafrole metabolite complex can be brought about by incubation with certain type I ligands. The capacity of isosafrole and piperonyl butoxide to induced cytochrome P-450 was evaluated by measurement of biphenyl 2- and 4-hydroxylase, ethoxyresofurin O-deethylase and ethylmorphine N-demethylase and by sodium dodecyl sulphate (SDS) polyacrylamide gel electrophoresis and compared with results obtained for phenobarbitone, 3-methylcholanthrene and pregnenolone-16 alpha-carbonitrile. All four monooxygenase activities were elevated by isosafrole and piperonyl butoxide, as were cytochrome P-450 levels in both strains of mice. There was a large increase in biphenyl 2-hydroxylase in microsomes from isosafrole treated mice of both strains on displacement of the metabolite complex. SDS polyacrylamide gel electrophoresis demonstrated that isosafrole and piperonyl butoxide induce protein bands of mol. wt., 54000 in both the responsive and non-responsive strains. In addition, piperonyl butoxide induces a protein band of mol. wt. 49000 in both strains of mice. The changes in metabolic activities on pretreatment with isosafrole and piperonyl butoxide do not correspond to those seen with any single inducing agent. The differences in the inducing capabilities of isosafrole and 3-methylcholanthrene in the 'non-responsive' DBA/2 strain are discussed with reference to possible mechanisms of induction by benzodioxole (methylenedioxyphenyl) compounds.

Animals↗
PubMed1987

Comparison of pediculicidal and ovicidal effects of two pyrethrin-piperonyl-butoxide agents.

A pyrethrin-piperonyl-butoxide shampoo was compared with a similarly formulated lotion for their pediculicidal and ovicidal effects against head lice. Forty children with active Pediculus humanus capitis infestation were randomly assigned to one of two groups for a single treatment with either the shampoo or the lotion. An average of ten nits were taken from each patient both before and after treatment. These eggs were incubated for 14 days, the resulting lice counted, and their conditions noted. Lice recovered from the rinse water after treatment were also counted and observed. Although both products proved to be effective in killing lice, the shampoo had greater ovicidal efficacy, 50% versus 25% for the lotion, after adjustment for natural mortality of the ova.

Administration, Topical↗