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PubMedDate not supplied

[Retinylpalmitate-hydrolase activity of the intestine in experimental lambliasis].

The retinylpalmitate-hydrolase activity in the small intestine of healthy and lambliae infected rats was determined. Infection of rats with Giardia lambliae is shown to result in a fall of the retinylpalmiate-hydrase activity, which is restored, in part, on application of a specific therapy (0.1 g/kg of chinacrine) and then practically does not differ from that in healthy animals, when the specific therapy is employed in conjunction with an elevated dose of the vitamin "A" (2000 m. u. of retinyl-palmitate per day).

Animals↗
PubMed1992

[The effect of foreign-substance-metabolizing enzymes on skin diseases].

Multiple drug-metabolizing enzymes are located in the skin of animals and humans: cytochrome P-450, epoxide hydrases, transferases and reductases. The distribution of cytochrome P-450 in the skin is not homogeneous; rather, it is more active in the basal epidermis, keratinocytes of the hair follicle, and sebaceous cells. The activity of drug-metabolizing enzyme can be induced, but it can also be inhibited by multiple endogenous and exogenous compounds. These enzymes detoxify many xenobiotics, but if the balance is disturbed there is the risk that xenobiotics will be activated to highly toxic compounds, which are even involved in the pathogenesis of skin cancer. Recent results indicate that cytochrome P-450 isoenzymes are also involved in the pathogenesis of psoriasis and drug-induced skin diseases.

Animals↗
PubMed1991

Role of ring oxidation in the metabolic activation of 1-nitropyrene.

Nitrated polycyclic aromatic hydrocarbons are wide-spread environmental pollutants that have been detected in photocopier toners, airborne particulates, coal fly ash, and diesel engine exhaust emissions. 1-Nitropyrene, a representative nitropolycyclic aromatic hydrocarbon present in diesel particulates, is a mutagen in Salmonella typhimurium and a tumorigen in laboratory animals. The activation of 1-nitropyrene to a bacterial mutagen has been attributed to nitroreduction; however, the metabolic pathways involved in its metabolism to a tumorigen are not known, but may involve nitroreduction, ring oxidation, or a combination of the two. In these experiments, we examined the importance of ring oxidation in the activation of 1-nitropyrene (99.85 to 99.98 percent 1-nitropyrene, 0.15 to 0.02 percent 1,3-, 1,6-, and 1,8-dinitropyrene by mass spectral analyses) to a mammalian-cell mutagen and carcinogen. Chinese hamster ovary cells were used to assess the mutagenicity of ring-oxidized 1-nitropyrene metabolites. In the absence of a rat liver 9,000 x g supernatant, 6-hydroxy-1-nitropyrene, 1-nitropyrene-9,10-oxide, and pyrene-4,5-oxide were the most mutagenic compounds tested. 3-Hydroxy-1-nitropyrene, 8-hydroxy-1-nitropyrene, and 1-nitropyrene-4,5-oxide were weaker mutagens, whereas pyrene and 1-nitropyrene were essentially nonmutagenic. The order of mutagenic potency with S9 was: 1-nitropyrene-4,5-oxide greater than 6-hydroxy-1-nitropyrene approximately 1-nitropyrene-9,10-oxide greater than 1-nitropyrene approximately 3-hydroxy-1-nitropyrene approximately 8-hydroxy-1-nitropyrene greater than pyrene approximately pyrene-4,5-oxide, with the last two compounds being nearly nonmutagenic. The epoxide hydrase inhibitor 1,2-epoxy-3,3,3-trichloropropane increased the mutation frequency fivefold. In addition, guinea pig liver microsomes and Aroclor-induced rat liver microsomes, which increased the formation of 1-nitropyrene-4,5-oxide and 1-nitropyrene-9,10-oxide, increased the mutagenic response. Incubation of 1-nitropyrene-4,5-oxide with calf thymus DNA resulted in the formation of three DNA adducts. A similar adduct pattern was observed when Chinese hamster ovary cells were incubated with the oxide. Inclusion of a nitroreductase, xanthine oxidase, in the in vitro incubations resulted in the formation of an additional adduct identified as N-(deoxyguanosin-8-yl)-1-aminopyrene. This adduct was not observed in Chinese hamster ovary cells treated with 1-nitropyrene-4,5-oxide. 1-Nitropyrene-9,10-oxide reacted with calf thymus DNA to give an adduct pattern similar to that observed with 1-nitropyrene-4,5-oxide. The distribution of adducts was not affected by conducting the reactions in the presence of xanthine oxidase.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1990

[Benzo(a)pyrene metabolism in human fibroblasts--effect of 7,8-benzoflavone].

Benzo(a)pyrene (BP) metabolism was studied in cultured fibroblasts from healthy donor. Cells were cultured in Eagle medium supplemented with 10% fetal calf serum, 2 mM 1-glutamine, 100 U/ml penicillin and 100 micrograms/ml streptomycin. Cultures were grown at 37 degrees C to confluence in 45 cm2 culture flasks containing 15 ml medium and refed with fresh medium 24 h prior to treatment with BP. Cells were treated for 24 h with [G-3H]BP diluted with BP to give a final concentration 10 microM and a specific activity of 0.3 Ci/mmol. The metabolites were extracted by ethyl acetate, dried with Na2SO4, evaporated with nitrogen and injected into high pressure liquid chromatograph. The column (LiChrosorb RP 18) was eluted with a linear gradient of 60% methanol in water to 100% methanol in 45 min at a flow rate 0.8 ml/min. Radioactivity of fractions was measured. Following metabolites were identified: 3-hydroxy-BP (23.7%), 9-hydroxy-BP (17.0%), quinones (22.9%), 7,8-dihydroxy-BP (6.1%), 9,10-dihydroxy-BP and other derivatives (30.3%). 7,8-benzoflavone--an inhibitor of BP hydroxylase and epoxide hydrase, strongly inhibited the metabolism of BP in human fibroblasts, changing the proportions in the amounts of the metabolites. The ratio of phenols to the other metabolites increased twice under the influence of 7,8-benzoflavone. This suggests that 7,8-benzoflavone has the stronger inhibitory effect on epoxide and diol formation in comparison with BP hydroxylation.

Benzo(a)pyrene↗
PubMedDate not supplied

Disposition of cyproheptadine in rats, mice, and humans and identification of a stable epoxide metabolite.

Radioactivity was excreted in the urine and feces of rats, mice, and humans after a dose of 14C-cyproheptadine. The major metabolite in rat urine was unconjugated, but the majority of radioactive materials in mouse and human urine were conjugated with glucuronic acid. Identification of the rat urinary metabolite of cyproheptadine as an epoxide was accomplished with mass spectrometry and other methods. The rat metabolite was 10.11 -epoxydesmethylcyproheptadine and accounted for about 25% of a 45-mg dose of cyproheptadine per kg. Only a small amount of this epoxide was found in mouse urine, and none was apparent in the urine of two humans who received 5 mg of the drug. Dihydrodiols, which could arise by epoxide hydrase hydrolysis of possible 10.11-epoxy metabolites, were not found in the urine of any of the species studied. The spoxide found in rat urine appears to be unusually stable to in vivo hydrolysis. Possible implications of these results in the species-selective pancreotoxicity of cyproheptadine in the rat are presented.

Adult↗
PubMed1975

Properties of aryl hydrocarbon (benzo[a]pyrene) hydroxylase in the liver from C3H/He and DBA/2 strains of mice.

Aryl hydrocarbon hydroxylase activity in liver from the C3H/He strain of mice is apparently increased by the administration of 3-methylcholanthrene, but the enzyme activity from the DBA/2 strain of mice is not. The enzyme activity from female mice is higher than that from male mice, even 72 hr after a single application of 3-methylcholanthrene into the mice. The control enzyme in the liver from both strains of mice has a pH optimum at 7.9 and the induced enzyme from C3H/He mice, at 8.2. There are approximately the same levels of the apparent Km for benzo[a]pyrene, NADPH, or NADH in the liver enzyme from both strains of mice even after treatment with 3-methylcholanthrene. The induced enzyme is inhibited by 7,8- or 5,6-benzoflavone non-competitively, and nicotinamide inhibits both the constitutive and induced enzyme uncompetiviely. Cyclohexene oxide and 1,1,1-trichloropropane oxide, known to be inhbitors of epoxide hydrase, inhibit the activity of the constitutive enzyme, but enhance the induced enzyme in the liver. The difference in the properties between the constitutive and induced enzymes from mouse liver is discussed briefly.

Animals↗
PubMed1989

DNA binding by 1-nitropyrene and dinitropyrenes in vitro and in vivo: effects of nitroreductase induction.

1-Nitropyrene, the predominant nitropolycyclic aromatic hydrocarbon found in diesel exhaust, is both a mutagen and a tumorigen. 1,6-Dinitropyrene is present in diesel exhaust in much smaller quantities than is 1-nitropyrene, but is much more mutagenic and carcinogenic. In an attempt to understand this difference in biological potencies, we have compared the extents to which these two nitropyrenes bind DNA in vivo. We have also determined the effect of 1-nitropyrene pretreatment upon the induction of nitroreductases and the subsequent DNA binding by both 1-nitropyrene and 1,6-dinitropyrene. In subsequent experiments, we have examined the importance of acetylation phenotype in the formation of DNA adducts from dinitropyrene in vivo. After a single intraperitoneal injection of 1-nitropyrene, covalent DNA binding could not be detected in vivo; however, 1,6-dinitropyrene formed N-(deoxyguanosin-8-yl)-1-amino-6-nitropyrene as the major DNA adduct in rat liver, kidney, urinary bladder, and mammary gland, with the highest levels being found in the bladder. The capability of liver microsomes to catalyze the oxidative metabolism of 1-nitropyrene was unchanged after treating rats with a single dose of 8 mg of 1-nitropyrene per kilogram of body weight. Cytochrome P-450, reduced nicotinamide adenine dinucleotide phosphate (NADPH2)-cytochrome P-450 reductase, and cytochrome b5 levels were also unchanged, while slight increases were detected in reduced nicotinamide adenine dinucleotide (NADH)-cytochrome b5 reductase and epoxide hydrase activities. Liver cytosolic and microsomal nitroreductase activities toward both 1-nitropyrene and 1,6-dinitropyrene were increased twofold, and cytosolic nitrosoreductase activity toward 1-nitrosopyrene and 1-nitro-6-nitrosopyrene was elevated by about 20 percent. DNA binding of both 1-nitropyrene and 1,6-dinitropyrene in vitro was twofold higher when cytosol from rats pretreated with 1-nitropyrene was used. However, pretreatment of rats with 1-nitropyrene only slightly increased the amount of in vivo DNA binding by 1,6-dinitropyrene except in the kidney, where there was a 60 percent increase. In the presence of S-acetylcoenzyme A, liver cytosol from slow-acetylator phenotype hamster strains Bio. 1.5 and 82.73 catalyzed the binding of two-to-three times more 1,8-dinitropyrene to DNA than was observed with the fast-acetylator phenotype strain Bio. 87.20. Similarly, when 1,8-dinitropyrene was administered in vivo and the extent of binding was assayed in liver, bladder, and intestinal DNA, there was more binding in strain Bio. 1.5 than in strain Bio. 87.20.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1978

Reduced nicotinamide adenine dinucleotide phosphate-dependent formation of 2,3-dihydro-2,3-dihydroxyaflatoxin B1 from aflatoxin B1 by hepatic microsomes.

2,3-Dihydro-2,3-dihydroxyaflatoxin B1 (dihydrodiol) was formed as a major metabolite in the incubation of aflatoxin B1 with rat and hamster liver microsomes. The yield of the dihydrodiol was maximal at pH 6.5, was reduced nicotinmide adenine dinucleotide phosphate- and cytochrome P-450-dependent, and was increased 2- to 4-fold by pretreatment of the animals with phenobarbital; pretreatment with 3-methylcholanthrene did not alter the activity of rat hepatic microsomes. Inhibitors of epoxide hydrase did not lower the yield of the dihydrodiol in these systems. Negligible yields of the dihydrodiol were formed from aflatoxin B1 and rat liver microsomes in the presence of DNA. Little or no formation of the dihydrodiol was noted with microsomes from rat intestinal mucosa, kidney, or lung. These results further support the formation of aflatoxin B1 2,3-oxide as a major electrophilic metabolite of aflatoxin B1 in rat and hamster liver microsomal systems, since this highly reactive epoxide would be expected to hydrolyze readily to form the dihydrodiol.

Aflatoxins↗
PubMed1987

[Effects of the ingestion of oxidized fish oils on hepatic microsomal enzyme activities and membrane fluidity in rats. Influence of tocopherol overload].

Rats fed a dietary peroxidized fish oil showed an increase in cytochrome P-450 content and ethoxy-coumarin deethylase (ECDE) activity in liver microsomes. Administration of DL-alpha-tocopherol led to different effects according to the extent of the peroxidation in the fish oil. In rats fed a de-peroxidized oil, the inductive effect of phenobarbital on UDP-glucuronosyltransferase (UDGPT) activity was depressed by tocopherol. By the same time, induction of P-450 and ECDE remained unchanged, that of epoxide hydrase slightly increased. By contrast tocopherol strongly potentiated the inductive effect of phenobarbital toward UDPGT activity (group I substrates) in rats fed the peroxidized fish oil. The modification of the inductive effect of phenobarbital in combination with tocopherol on UDPGT activities was concomitant with an increase in seric transaminase activity and with a reverse effect as revealed from the study of the rate of fluorescent probes penetration in microsomes. The possible toxicity of the strong dose of tocopherol is discussed.

Animals↗
PubMed1988

[Ingestion of soybean epoxide oil. Effects on monooxygenases, epoxide hydrolase and activities of UDP glucuronosyltransferases in hepatic microsomes of the rat].

The effect of peroxidized soybean oil in the diet of male Wistar rats was studied on hepatic drug metabolizing enzymes and their phenobarbital induction and compared to that of natural soybean diet in the same conditions. No hepatomegaly or increase in serum transaminases occurred, however growth was inhibited after ingestion of peroxidized soybean oil. In addition, the protein biosynthesis of epoxide hydrase determined by immunochemistry was largely stimulated by this treatment; but the corresponding activity measured with benzo(a)pyrene 4-5 oxide as a substrate was increased in weaker proportions. This induction was limited to epoxide hydrolase only, since the enzymes of phase one were not affected and UDP glucuronosyltransferase activities toward group I substrates were randomly activated. The induction of epoxide hydrolase may affect only one or several isoforms of the membrane enzyme which are not necessarily specific to benzo(a)pyrene 4-5 oxide activity determination of the enzyme.

Animals↗
PubMed1978

Pulmonary metabolism of epoxides.

Activities of epoxide hydrase (EH) and glutathione S-transferase (GST) have been measured in pulmonary tissue from several species. On the basis of total organ activity, pulmonary tissue has less capacity than liver tissue to metabolize epoxides. Pulmonary EH and GST appear to be refractory to induction by typical agents. Rat pulmonary GST will conjugate a variety of epoxides, but K-region epoxides are metabolized at lower rates than alkene oxides. In the isolated perfused rabbit lung, benzo (a) pyrene-4,5-oxide (BPO) is metabolized by EH and GST at similar initial rates, but EH activity is lost after a few minutes, apparently owing to inadequate local substrate levels. GST from rabbit lung cytosol has been separated by chromatographic methods into six peaks of enzymic activity (toward 1-chloro-2,4-denitrobenzene). Of these peaks, all six metabolized BPO and two metabolized styrene oxide. Although EH and GST are less active in lung than in liver, pulmonary metabolism of epoxides is important because this tissue must be able to protect itself from arene oxides generated by pulmonary oxidative metabolism of polycyclic aromatic hydrocarbons.

Animals↗
PubMedDate not supplied

The biotransformation of allyl alcohol and acrolein in rat liver and lung preparations.

The biotransformation of allyl alcohol and acrolein by rat lung and liver preparations was investigated by measuring acrolein, acrylic acid, glycidol, and glycidaldehyde. Acrolein was detected by high-pressure liquid chromatography from incubation mixtures containing allyl alcohol, NAD+, and liver 9000g supernatant fraction or cytosol. Acrolein was not formed when lung fractions were treated similarly. Addition of pyrazole in the incubation mixture inhibited the reaction. The metabolism of acrolein to acrylic acid by liver 9000g supernatant fraction, cytosol, and microsomes has been demonstrated; acrylic acid formation was greater with NAD+ than with NADP+ in all three fractions. Acrylic acid was also formed from allyl alcohol. Disulfiram inhibited the NAD+- and NADP+-dependent reactions. Acrylic acid was not formed when lung preparations were used. Lung and liver microsomal epoxidation products of allyl alcohol and acrolein have been identified. Conversion of glycidol to glycerol and glycidaldehyde to glyceraldehyde by liver epoxide hydrase has been demonstrated. Epoxides, glycidol, and glycidaldehyde were also found to be substrates for lung and liver cytosolic glutathione S-transferase.

1-Propanol↗
PubMed1980

The deacetylation of N-hydroxy-2-acetylaminofluorene by rat liver microsomes and carboxyl esterase.

We have demonstrated that incubation of rat liver microsomes with N-hydroxy-2-acetylaminofluorene (N-OH-AAF) leads to formation of a 2-nitrosofluorene-membrane lipid adduct. This adduct exists as a nitroxyl free radical, termed N-O-LAF, in its oxidized state. When microsomes were incubated with the sulfhydryl binding agent, rho-hydroxymercuribenzoate, a larger amount of N-OL-LAF formed. We interpret this as a slowdown in the rate of endogenous chemical reduction of carcinogen-membrane lipid adduct. In this paper we present evidence that N-OH-AAF is deacetylated by a microsomal enzyme to form N-hydroxy-2-aminofluorene and this is then oxidized to 2-nitrosofluorene which adds covalently to membrane lipid double bonds to form N-O-LAF. Various antioxidants, peroxidase inhibitors, and P450 substrates and inhibitors were ineffective in altering the amount of N-O-LAF formed from N-OH-AAF; but two esterase inhibitors, dietyl-rho-nitrophenylphosphate and alpha-toluene-sulfonyl fluoride, prevented N-O-LAF formation. Of the following purified enzymes tested: porcine liver carboxyl esterase, pepsin, chymotrypsin, cathepsin D, ficin, papain, leucine aminopeptidase, Naja naja phospholipase, acetylcholinesterase (type I), trypsin (type I and V) and epoxide hydrase; only carboxyl esterase was effective in deacetylating N-OH-AAF.

2-Acetylaminofluorene↗
PubMed1984

Pharmacological characterization of teroxirone, a triepoxide antitumor agent, in rats, rabbits, and humans.

Teroxirone is an experimental triepoxide antitumor agent currently undergoing evaluation in clinical trials. We have developed an assay based on derivatization with diethyldithiocarbamate followed by normal-phase high-performance liquid chromatographic analysis. When 14C-labeled teroxirone is administered to rabbits by rapid i.v. infusion, plasma disappearance of parent drug is very rapid (t1/2 less than 5 min), while plasma 14C-labeled drug equivalents are eliminated at a much slower rate (t1/2 greater than 60 min). Twenty-four-hr urinary recovery of parent drug is less than 1%, while recovery of 14C total radioactivity is 60 to 70%. Rapid plasma elimination (t1/2 less than 5 min) and total body clearance (greater than 5 liters/min) are observed following rapid i.v. administration of teroxirone to humans. When teroxirone is administered to humans at constant rates of infusion, plateau concentrations are rapidly achieved and maintained during infusion. Plasma concentrations rapidly decrease upon cessation of infusion. Less than 1% parent drug is recovered in 24-hr urine. Teroxirone is relatively stable in fresh human plasma and whole blood. Teroxirone is metabolized by rat liver, but not lung, microsomal preparations by an NADPH-independent pathway. Epoxide hydrolysis metabolites are detected in microsomal incubations, and cyclohexene oxide inhibits teroxirone metabolism, suggesting that epoxide hydrase may be responsible for teroxirone biotransformation. Cytotoxicity of teroxirone against continuous human tumor cell lines is abolished in the presence of 9000 X g rat liver supernatant preparations but partially restored when cyclohexene oxide is added to incubation mixtures.

Animals↗
PubMed1980

Hormonal regulation of cytochrome P-450-dependent monooxygenase activity and epoxide-metabolizing enzyme activities in testis of hypophysectomized rats.

Since the male gonad is a target organ of both pituitary hormones and androgens, the present study was performed to determine whether testicular aryl hydrocarbon hydroxylase (AHH), epoxide hydrase (EH), and glutathione transferase activities and cytochrome P-450 levels were regulated by follicle-stimulating hormone (FSH), luteinizing hormone (LH), and testosterone. Intact, sham-operated controls and hypophysectomized (HYPOX) male rats were used. Forty days after HYPOX, rats received three daily injections of LH, FSH, testosterone, or LH plus FSH (100 microgram each), or 0.15 M NaCl. Rats were killed 5, 10, and 15 days after hormone administration. In HYPOX rats, testicular AHH and EH activities and P-450 content were significantly reduced at all time points (20 to 70% of sham-operated control values), but glutathione transferase activity was unchanged. In contrast, testicular AHH, EH, and P-450 were significantly induced in all LH treatment groups but not in FSH or testosterone treatment groups. The highest induction with LH was found in the 15-day treatment group (5- to 14-fold that of 0.15 M NaCl-treated HYPOX control). Since Leydig cells are target cells of LH, the result suggests that LH-stimulated induction of testicular AHH and EH activities and P-450 contents may be primarily associated with the interstitial cell compartment.

Animals↗
PubMed1982

Metabolism of polycyclic aromatic hydrocarbons and covalent binding of metabolites to protein in rat adrenal gland.

The metabolism of the carcinogenic and adrenocorticolytic polycyclic aromatic hydrocarbon 7,12-dimethylbenz(a)anthracene in rat adrenals was investigated. Both 7,12-dimethylbenz(a)anthracene and benzo(a)pyrene, which also is a well-known carcinogen but has no short-term effects on rat adrenals, appear to be metabolized by one common type of cytochrome P-450-dependent monooxygenase localized in the endoplasmic reticulum. Studies of the kinetic properties of this cytochrome P-450 reveal that the Km values for 7,12-dimethylbenz(a)anthracene and benzo(a)pyrene are lower than 3 microM. Identification of metabolites indicates that, with both 7,12-dimethylbenz(a)anthracene and benzo(a)pyrene, phenols and diols were formed the relative rates of formation of which were markedly influenced by the expoxide hydrase inhibitor cyclohexane oxide, suggesting that epoxides are intermediate metabolites. Added or endogenous microsomal glutathione S-transferase B had little or no effect on the distribution of metabolites. A rather selective binding of metabolites of 7,12-dimethylbenz(a)anthracene to soluble and microsomal proteins was demonstrated. The adrenal cytochrome P-450 involved in the conversion of these polycyclic aromatic hydrocarbons appears to be unrelated to those responsible for the synthesis of mineralocorticoids and glucocorticoids from cholesterol. Among androgens and estrogens, estradiol proved to be the most inhibitory steroid, suggesting a role of the hydrocarbon-metabolizing cytochrome P-450 in estrogen biosynthesis. However, no such function could be demonstrated conclusively. The metabolite patterns and the effects of nonsteroid inhibitors of liver monooxygenases, e.g., alpha-naphthoflavone, SU 9055, and ellipticine, suggest that the properties of this cytochrome P-450 resemble those of the 3-methyl-cholanthrene-inducible cytochrome P-488 from rat liver.

9,10-Dimethyl-1,2-benzanthracene↗