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At least 19 recordsLinked to original sources
PubMed1997

Clustered binary logistic regression in teratology data using a finite mixture distribution.

The beta-binomial distribution introduced by Skellam has been applied in many teratology problems for modelling the litter effect. Recently, Morel and Nagaraj proposed a new distribution for modelling cluster multinomial data when the clustering is believed to be caused by clumped sampling. It turns out that the distribution is a mixture of two binomial distributions and accommodates the estimation of an additional parameter to account for intra-litter effect. The new distribution arises from a cluster mechanism in which some individuals within a cluster exhibit the same behaviour while the remaining individuals from the cluster react independently of each other. Such a mechanism is a natural model in teratology problems, where typically a genetic trait is passed with a certain probability to the foetuses of the same litter. In this article, we use the new distribution to model binary responses with logistic regression. We analyse data from a teratology experiment to demonstrate that the new model provides a useful addition to current methodology. The experiment investigates the synergistic effect of the anticonvulsant phenytoin and trichloropopene oxide on the prenatal development of inbred mice. In a simulation study we investigate the type I error rate and the power of the maximum likelihood ratio test when the data follow a finite mixture distribution.

Animals↗
PubMed1993

Base-pair mutations caused by six aliphatic epoxides in Salmonella typhimurium TA100, TA104, TA4001, and TA4006.

Salmonella typhimurium strains TA100, TA104, TA4001, and TA4006 were used to detect the base-pair mutations caused by six aliphatic epoxides: chloropropylene oxide, glycidyl 1-naphthyl ether, glycidyl 4-nitrophenyl ether, 1-naphthyl-propylene oxide, styrene oxide, and trichloropropylene oxide. Dose-mutagenicity relationships could be established for all six epoxides in strains TA100 and TA104 but not in strains TA4001 and TA4006. These results, together with the lack of sensitivity of the TA100 revertants to DL-1,2,4-triazole-3-alanine, indicate CG-->TA transitions and/or CG-->AT transversions are of major importance for mutations induced by these epoxides in Salmonella TA100 and possibly TA104. In addition, since the reproducibility of the effect of the triazole on TA104 reversions was poor, TA-->AT transversions were not eliminated as also contributing to the mutagenicity of these epoxides in this Salmonella strain.

Epoxy Compounds↗
PubMed1995

Phenytoin embryopathy: effect of epoxide hydrolase inhibitor on phenytoin exposure in utero in C57BL/6J mice.

Previous animal research has suggested that the phenytoin arene oxide metabolite is teratogenic in acute studies and that the fetal effects were increased after injecting an inhibitor of microsomal epoxide hydrolase (mEH) (Martz et al., Pharmacol Exp Ther 203:231-239, 1977, Barcellona et al., Teratog Carcinog Mutagen 7:159-168, 1987). We have studied the effects of chronic oral phenytoin exposure in utero and the mEH inhibitor trichloropropene oxide (TCPO) on the prenatal growth and development of an inbred mouse strain with a low incidence of spontaneous oral clefting (C57BL/6J). Chronic daily gastric gavage of phenytoin produced a plasma level (mean 10.7 micrograms/ml on gestation Day 8) within the range recommended to prevent epilepsy in humans; this did not produce an increase in oral clefting or ventricular septal defects in the exposed C57BL/6J pups. It did produce a significant delay in prenatal growth and development, including phalangeal ossification. However, except for percentage resorptions/implantation, there was no synergism between phenytoin and TCPO in contrast to the finding reported by Martz et al. in Swiss mice. This issue was also assessed in a test of the fetal effect of phenytoin injected with TCPO, as had been done by Martz et al. There were no oral clefts or ventricular septal defects or a difference (P > 0.05) in prenatal growth and development in these C57BL/6J pups compared to the chronic gastric phenytoin plus TCPO group. This suggests either that differences in the genotypes of Swiss and C57BL/6J mice may be a contributing factor or that other teratogenic mechanisms were involved.

Animals↗
PubMed1985

Covalent binding of BP-metabolites to DNA of cultured human hair follicle keratinocytes.

Primary cultures of human hair follicle keratinocytes were established by using a basement membrane-like growth substrate, the bovine eye lens capsule. A method was adapted for the isolation of 3H-benzo(a)pyrene (BP)-modified DNA from the cellular outgrowth of only one hair follicle (approximately 2 X 10(5) cells). In a routine procedure hair follicle keratinocytes were incubated with 0.5 microM 3H-BP for 24 h. The purified DNA was subjected to enzymic hydrolysis and the adducts were analyzed by Sephadex LH-20 column chromatography followed by HPLC. Only one major adduct, which represented 60-80% of the total radioactivity which can be confined to modified nucleosides in the LH-20 chromatograph, could be identified. This adduct co-chromatographed with the marker adducts resulting from the trans-addition of the N-2-amino group of guanine to the 10-position of (+/-)-7 beta,8 alpha-dihydroxy-9 alpha,10 alpha-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene. Co-incubation with 7,8-benzoflavone (0.3 microM), an inhibitor of cytochrome P-448, and with 1,1,1-trichloropropene-2,3-oxide (0.2 microM), an inhibitor of epoxide hydrolase, resulted in a marked inhibitory effect (15% of the control binding) and a large increase (300% of the control value) in BP-DNA binding respectively. Induction of aryl hydrocarbon hydroxylase activity in the cultures with 5,6-benzoflavone (10 microM) or benz(a)anthracene (10 microM) caused a decrease (75 and 46% of the control value respectively) in BP-DNA binding.(ABSTRACT TRUNCATED AT 250 WORDS)

Benzo(a)pyrene↗
PubMed1980

Dose-dependent effect of trichloropropene oxide on benzo[a]pyrene carcinogenesis.

The epoxide hydratase inhibitor, 1,1,1-trichloro-2,3-propene oxide (TCPO) in combination with benzo[a]pyrene (B[a]P) was injected s.c. in ddN mice. The formation of fibrosarcoma by B[a]P was slightly accelerated at low dose of TCPO, and remarkably inhibited at high dose of TCPO. The correlation of carcinogenesis with B[a]P metabolism was discussed.

Animals↗
PubMed1983

Activation and deactivation of aflatoxin B1 in isolated rat hepatocytes.

Isolated rat hepatocytes took up [3H]-aflatoxin B1 during incubation with fifty percent of the aflatoxin B1 covalantly bound to cellular macromolecules. The amount of bound-aflatoxin B1 was proportional to the medium concentration of aflatoxin B1. The specific radioactivity (pmole/mg) of aflatoxin B1 found in the DNA fraction was 20 fold greater than that associated with protein. Metyrapone (0.75 mM) inhibited significantly the uptake and binding whereas 1,2-epoxy-3,3,3-trichloropropane (0.5 mM) enhanced 2-3 fold both the uptake and binding. Glutathione (0.25 mM) reduced these processes. Results indicate that a transformation of aflatoxin B1 is catalyzed by cytochrome P-450 mixed function oxidase and aflatoxin B1-2,3-epoxide so formed is primarily deactivated by epoxide hydrolase. In the isolated hepatocyte depletion of the epoxide by glutathione apparently has an insignificant role in aflatoxin detoxication.

Aflatoxin B1↗
PubMed1982

Metabolism of benzo [a] pyrene by guinea pig adrenal and hepatic microsomes.

Studies were carried out to compare the metabolism of benzo [a] pyrene (BP) by adrenal and hepatic microsomes obtained from adult male guinea pigs. Adrenal microsomes produced fluorescent metabolites (primarily phenols) approximately three to four times more rapidly than hepatic microsomes, but the differences in the rates were considerably smaller when total BP metabolism was assessed using an isotopic assay. The apparent discrepancy between the two assays is attributable to differences in the profiles of BP metabolites produced by adrenal and liver. Separation of metabolites by high pressure liquid chromatography revealed that adrenal microsomes converted BP to primarily a phenolic metabolite with a retention time identical to that of 3-hydroxy-BP. Liver microsomes, by contrast, produced approximately equal amounts of compounds co-chromatographing with 3-hydroxy-BP and BP-4,5-dihydrodiol. Small amounts of other metabolites were also produced by adrenal and hepatic microsomes. Liver microsomes catalyzed the conversion of BP to metabolites that became covalently bound to exogenous DNA. The amount of binding was dependent upon the duration of incubation and concentration of microsomal protein. Adrenal microsomes, by contrast, did not promote BP binding to DNA. Inhibition of microsomal epoxide hydratase activity with trichloropropene oxide (TCPO) blocked the formation of dihydrodiol metabolites of BP by adrenal and liver microsomes. In the presence of TCPO, liver microsomes produced large amounts of a BP metabolite co-chromatographing with BP-4,5-oxide. TCPO also increased the rate of production of DNA-binding metabolites by liver microsomes but had no effect on the formation of DNA-binding metabolites by adrenal microsomes. The results demonstrate major differences in the pathways of BP metabolism by guinea pig adrenal and hepatic microsomes. Although adrenal microsomes metabolize BP more rapidly than hepatic microsomes, far greater amounts of reactive metabolites are produced by the liver. Thus, adrenal metabolism of BP may be of little toxicological significance.

Adrenal Glands↗
PubMed1985

Vitamin K epoxide reductase activity in the metabolism of epoxides.

The importance of vitamin K epoxide reductase for the metabolism of a range of structurally diverse epoxides has been investigated. Vitamin K1 epoxide is reduced by rat liver microsomes at a rate of 0.47 nmoles/g liver/min. The rate of menadione oxide reduction is not significantly higher than the non-enzymatic reduction rate. No measurable reduction of benzo[a]pyrene 4,5-oxide, benzo[a]pyrene 7,8-oxide, phenanthrene 9,10-oxide, styrene 7,8-oxide, and dieldrin has been detected, nor could trichothecene T-2 toxin inhibit reduction of vitamin K1 epoxide. Thus, vitamin K epoxide reductase is very specific for vitamin K1 epoxide. Taking into account the range of structurally diverse epoxides investigated and the high specific activities of microsomal epoxide hydrolase and cytosolic glutathione transferase for these epoxides it may be concluded that vitamin K epoxide reductase, in all likelihood, generally does not significantly contribute to the control of epoxides metabolically formed from xenobiotics.

Animals↗
PubMed1986

Characterization of multiple epoxide hydrolase activities in mouse liver nuclear envelope.

A nuclear envelope-associated epoxide hydrolase in mouse liver that hydrates trans-stilbene oxide has been identified and characterized. This epoxide hydrolase is distinct from the enzyme in nuclear envelopes that hydrates benzo[a]pyrene 4,5-oxide and other arene oxides. This distinction was demonstrated by the criteria of pH optima, response to specific inhibitors in vitro, and precipitation by specific antibodies. The new epoxide hydrolase had a pH optimum of 6.8, was poorly inhibited by trichloropropene oxide, was potently inhibited by 4-phenylchalcone oxide, and did not bind to antiserum against benzo[a]pyrene 4,5-oxide hydrolase. This nuclear enzyme is similar in many of its properties to cytosolic and microsomal trans-stilbene oxide hydrolases and may be nuclear envelope-bound form of these other epoxide hydrolases. It differed from these other trans-stilbene oxide hydrolases in that its affinities for both trans-stilbene oxide (measured as apparent Km) and 4-phenylchalcone oxide (measured as I50) were 4- to 20-fold lower than those of either the cytosolic or microsomal forms.

Animals↗
PubMed1993

An investigation of the formation of cytotoxic, genotoxic, protein-reactive and stable metabolites from naphthalene by human liver microsomes.

Chemically reactive epoxide metabolites have been implicated in various forms of drug and chemical toxicity. Naphthalene, which is metabolized to a 1,2-epoxide, has been used as a model compound in this study in order to investigate the effects of perturbation of detoxication mechanisms on the in vitro toxicity of epoxides in the presence of human liver microsomes. Naphthalene (100 microM) was metabolized to cytotoxic, protein-reactive and stable, but not genotoxic, metabolites by human liver microsomes. The metabolism-dependent cytotoxicity and covalent binding to protein of naphthalene were significantly higher in the presence of phenobarbitone-induced mouse liver microsomes than with human liver microsomes. The ratio of trans-1,2-dihydrodiol to 1-naphthol was 8.6 and 0.4 with the human and the induced mouse microsomes, respectively. The metabolism-dependent toxicity of naphthalene toward human peripheral mononuclear leucocytes was not affected by the glutathione transferase mu status of the co-incubated cells. Trichloropropene oxide (TCPO; 30 microM), an epoxide hydrolase inhibitor, increased the human liver microsomal-dependent cytotoxicity (19.6 +/- 0.9% vs 28.7 +/- 1.0%; P = 0.02) and covalent binding to protein (1.4 +/- 0.3% vs 2.8 +/- 0.2%; P = 0.03) of naphthalene (100 microM), and reversed the 1,2-dihydrodiol to 1-naphthol ratio from 6.6 (without TCPO) to 2.6, 0.6 and 0.1 at TCPO concentrations of 30, 100 and 500 microM, respectively. Increasing the human liver microsomal protein concentration reduced the cytotoxicity of naphthalene, while increasing its covalent binding to protein and the formation of the 1,2-dihydrodiol metabolite. Co-incubation with glutathione (5 mM) reduced the cytotoxicity and covalent binding to protein of naphthalene by 68 and 64%, respectively. Covalent binding to protein was also inhibited by gestodene, while stable metabolite formation was reduced by gestodene (250 microM) and enoxacin (250 microM). The study demonstrates that human liver cytochrome P450 enzymes metabolize naphthalene to a cytotoxic and protein-reactive, but not genotoxic, metabolite which is probably an epoxide. This is rapidly detoxified by microsomal epoxide hydrolase, the efficiency of which can be readily determined by measurement of the ratio of the stable metabolites, naphthalene 1,2-dihydrodiol and 1-naphthol.

Adult↗
PubMed1995

Kinetic parameters of lymphocyte microsomal epoxide hydrolase in carbamazepine hypersensitive patients. Assessment by radiometric HPLC.

Idiosyncratic hypersensitivity reactions with carbamazepine have been postulated to be due to a deficiency of microsomal epoxide hydrolase (HYL1), although this is based on indirect evidence. Using 3H-cis stilbene oxide (0.5 Ci/mmol) as a substrate, we have developed a radiometric HPLC assay sensitive enough to measure the kinetic parameters of HYL1 in lymphocytes. The intra-assay coefficient of variation was 8%. Enzyme activity has been measured in lymphocytes from six carbamazepine hypersensitive patients, six patients on carbamazepine without any adverse effects, and twelve drug-naive healthy volunteers. No significant difference was observed in three kinetic parameters of the enzyme among these three groups. The values for Km, Vmax, and intrinsic clearance ranged from 6.1-89.9 microM, 3.0-23.2 pmoles diol formed/min/mg protein, and 0.147-0.493 microliter/min/mg protein. There was no difference in enzyme activity between patients currently on carbamazepine and healthy volunteers, indicating a lack of induction of lymphocyte HYL1 by carbamazepine. Co-incubation of lymphocytes with 1,1,1-trichloropropene oxide, an inhibitor of hepatic HYL1, resulted in an 82% inhibition of activity, similar to that observed with the hepatic enzyme. The healthy volunteers were genotyped as being either GSTM1 positive (n = 6) or GSTM1 negative (n = 6). This did not affect the kinetic parameters of lymphocyte microsomal epoxide hydrolase. Our results suggest that there is normal HYL1 activity in lymphocytes of hypersensitive patients using cis-stilbene oxide as a substrate.

Adolescent↗
PubMed1979

Fluorescence study of DNA alkylation by epoxides.

A simple fluorescence assay was devised to measure alkylation of guanine. The assay was tested with simple epoxides: propylene oxide, glycidol, epichlorohydrin, trichloropropylene oxide and styrene oxide, which are known to vary considerably in their mutagenic potency. The order of reactivity parallelled the mutagenic potency, trichloropropylene oxide being the most reactive alkylating agent. Each epoxide alkylated deoxyguanosine faster than single-stranded DNA, at equal concentrations of guanine. Single-stranded DNA was alkylated substantially faster than was double-stranded DNA. The reaction products with each substrate were analysed by thin-layer chromatography and exhibited similar Rf-values. It was concluded that polymers, particularly double-stranded DNA, reacted slower than deoxyguanosine due to the properties of polymers in solution rather than the unavailability of reactive sites for alkylation.

1-Propanol↗
PubMedDate not supplied

Mouse liver microsomal cholesterol epoxide hydrolase: a specific inhibition of its activity by 5,6 alpha-Imino-5 alpha-cholestan-3 alpha-OL.

A comparative study on mouse liver epoxide hydrolase activities has been done by using enzyme inhibitors in order to obtain evidence for the specificity of microsomal cholesterol epoxide hydrolase. 5,6 alpha-Imino-5 alpha-cholestan-3 beta-ol (IC) strongly inhibited the microsomal hydrolysis of cholesterol alpha-epoxide and the other delta 5-steroid alpha-epoxides (0.1 mM each) at concentrations less than 1 microM but affected neither microsomal nor cytosolic hydrolysis of any other epoxides of endogenous and exogenous compounds (0.1 mM each). On the other hand, 3,3,3-trichloropropene 1,2-oxide (TCPO) did not inhibited the microsomal hydrolysis of delta 5-steroid alpha-epoxides but strongly inhibited both microsomal and cytosolic hydrolysis of the other epoxides used. The only exceptions for the epoxy substrates that were not affected by both inhibitors were 5 alpha-cholest-2-ene alpha- and beta-epoxides. The inhibition by IC of the microsomal cholesterol alpha-epoxide hydrolysis was competitive, but no significant inhibition of the enzyme activity was observed by the typical microsomal xenobiotic substrates, hexadecene oxide and benzo[a]pyrene 4,5-oxide. These results strongly suggest that the microsomal enzyme hydrolyzing cholesterol alpha-epoxide differs from the microsomal hydrolase for epoxides of various xenobiotic olefins and arenes.

Animals↗
PubMed1984

Characterization and quantitation of 3-alkylthymidines from reactions of mutagenic propylene oxides with thymidine.

Thymidine was reacted in methanol with four epoxides of varying mutagenicities: propylene oxide, glycidol, epichlorohydrin and trichloropropylene oxide. A single product was detected with each epoxide, and these products had the same retention times on silica high pressure liquid chromatography (HPLC). UV spectra of the products identified them as 3-alkylthymidines, and this was confirmed by infrared (IR) and nuclear magnetic resonance (NMR) spectra. Mass spectra (MS) analysis showed the products to be consistent with attachment at the least substituted carbon of the epoxide. Formation of 3-alkylthymidines correlated to Taft sigma electron withdrawing values for the substituents on the epoxides and mutagenicities in strain TA100 of the Ames Assay.

1-Propanol↗
PubMed1984

Reactivity of propylene oxides towards deoxycytidine and identification of reaction products.

Deoxycytidine was reacted with four epoxides of varying alkylating rates: propylene oxide, glycidol, epichlorohydrin and trichloropropylene oxide. Deoxycytidine was chosen to compare the reactivities of these epoxides as all sites of possible alkylation, the oxygen and both nitrogens, are involved in base pairing in DNA. Reaction products were separated on HPLC. Products of the least and most reactive epoxides, propylene oxide and trichloropropylene oxide, were characterized by UV, IR, 360 MHz NMR and MS analysis. For the epichlorohydrin and glycidol reactions and all analytical separations, products were characterized by their HPLC retention times and UV spectra. While differences in reactivity among the epoxides towards specific nitrogen and oxygen sites were found, total reactivity correlated with Taft sigma-values of the substituent groups.

Alkylation↗
PubMed1988

Microsomal metabolism of picene.

Picene, a polycyclic aromatic hydrocarbon (PAH) of environmental relevance has recently been predicted to be carcinogenic, based on quantum mechanical calculation, although in several animal studies no carcinogenicity could be detected. In order to find out if the metabolism of this PAH can provide an explanation for its lack of carcinogenicity, picene was incubated with the hepatic microsomal fraction of Sprague-Dawley rats, which had been pretreated with Aroclor 1254. Sixteen ethyl acetate-extractable metabolites could be separated by reversed-phase high-performance liquid chromatography. Comparison of the chromatographic behavior and the UV and mass spectral properties of the metabolites with those of synthetic derivatives of picene allowed the identification of trans-1,2-, -3,4-, -5,6-dihydrodiol as well as 2- and 4-phenol as microsomal metabolites of picene. At a substrate concentration of 2.7 microM and an amount of 68 micrograms microsomal protein per ml incubation volume, 4-picenol was the main microsomal metabolite with 32.2% of total metabolic conversion, followed by the 1,2-(bay-region)dihydrodiol with 16.7%, the 3,4-(M-region)dihydrodiol with 15.9%, 2-picenol with 9.1% and the 5,6-(K-region)dihydrodiol with 1.6%. In this respect the metabolism of picene is not significantly different from that of the carcinogenic PAH benzo[a]pyrene and dibenz[a,h]anthracene. The M-region dihydrodiols, potential precursors of electrophilically reactive dihydrodiol bay-region epoxides, are formed from all three PAHs at 11-16% of total metabolic conversion. From the 2.8- to 4.4-fold lower amounts of polar and water-soluble metabolites of picene as compared to dibenz[a,h]anthracene and benzo[a]pyrene it is deduced that dihydrodiol epoxides are generated from picene to a much smaller extent than from the two carcinogenic PAHs. The lacking carcinogenicity of picene could therefore result from the inability of microsomal enzymes to transform its M-region dihydrodiol to dihydrodiol bay-region epoxides in amounts necessary to initiate carcinogenesis.

Animals↗