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W Levin

Publications and source records attributed to W Levin.

At least 271 records · Page 15Linked to original sources
PubMed1977

Hydration of arene and alkene oxides by epoxide hydrase in human liver microsomes.

The comparative hydration of styrene 7,8-oxide, octene 1,2-oxide, naphthalene 1,2-oxide, phenanthrene 9,10-oxide, benzo[a]anthracene 5,6-oxide, 3-methylcholanthrene 11,12-oxide, dibenzo[a,h]anthracene 5,6-oxide, and benzo[a, 7,8-, 9,10-, and 11,12-oxides to their respective dihydrodiols was investigated in microsomes from nine human autopsy livers. The substrate specificity of the epoxide hydrase in human liver microsomes was very similar to that of the epoxide hydrase in rat liver microsomes. Phenanthrene 9,10-oxide was the best substrate for the human and rat epoxide hydrases and dibenzo[a,h]anthracene 5,6-oxide and benzo[a-a)pyrene 11, 12-oxide were the poorest substrates. Plotting epoxide hydrase activity obtained with one substrate against epoxide hydrase activity for another substrate for each of the nine human livers revealed excellent correlations for all combinations of the 11 substrates studied (r = 0.87 to 0.99). The data suggest the presence in human liver of a single epoxide hydrase with broad substrate specificity. However, the results do not exclude the possible presence in human liver of several epoxide hydrases that are under similar regulatory control. These results suggest the need for further investigation to determine whether there is a safe epoxide of a drug whose in vivo metabolism is predictive of the capacity of different individuals to metabolize a wide variety of epoxides of drugs and environmental chemicals.

Alkenes↗
PubMed1977

Mutagenicity and cytotoxicity of benz[alpha]anthracene diol epoxides and tetrahydro-epoxides: exceptional activity of the bay region 1,2-epoxides.

Three diastereomeric pairs of diol epoxides, two tetrahydro-epoxides, and the K-region oxide of the polycyclic aromatic hydrocarbon benz[a]anthracene were evaluated for mutagenic activity in strain TA 100 of Salmonella typhimurium and in line V79-6 of Chinese hamster lung cells. The two diastereomeric 1,2-epoxides of the trans-3,4-dihydrodiol of benz[a]anthracene are 15 to 35 times more mutagenic to the bacteria and 65 to 125 times more mutagenic to the mammalian cells than are the diastereomeric pairs of benz[a]anthracene-8,9-diol-10,11-epoxides or benz[a]anthracene-10,11-diol-8,9-epoxides. 1,2-Epoxy-1,2,3,4-tetrahydrobenz[a]anthracene is the most mutagenic and cytotoxic of the nine derivatives and is 5 and 25 times more mutagenic than 3,4-epoxy-1,2,3,4-tetrahydrobenz[a]anthracene in bacterial and mammalian cells, respectively. In either test system, benz[a]anthracene 5,6-oxide (K-region oxide) has less than 10% of the activity of any of the 1,2-epoxides derived from benz[a]anthracene. The relative stabilities of the derivatives in aqueous solution do not account for the differences in mutagenic activity because the more mutagenic derivatives tend to be less stable. The benz[a]anthracene diol epoxides, like the benzo[a]pyrene diol epoxides, are refractory to the action of epoxide hydrase. The exceptional mutagenic activity of the 1,2-epoxide derivatives of benz[a]anthracene is consistent with and supportive of the hypothesis that bay region epoxides on saturated, angular benzo-rings of unsubstituted polycyclic aromatic hydrocarbons are ultimate carcinogens.

Benz(a)Anthracenes↗
PubMed1977

Tumorigenicity of five dihydrodiols of benz(a)anthracene on mouse skin: exceptional activity of benz(a)anthracene 3,4-dihydrodiol.

Benz[a]anthracene and the five metabolically possible vicinal trans dihydrodiols of benz[a]anthracene were tested for ability to initiate skin tumors in CD-1 female mice. A single topical application of 0.4-2.0 mumol of hydrocarbon was followed 18 days later by twice weekly applications of the skin promoter 12-O-tetradecanoylphorbol-13-acetate. Comparisons of latency period, percent of mice with tumors, and number of papillomas observed per mouse indicated that benz[a]anthracene 1,2-, 5,6-, 8,9-, and 10, 11-dihydrodiols were all less active tumor initiators than was benz[a]anthracene. The high tumorigenicity of benz[a]anthracene 3,4-dihydrodiol, presumably the result of metabolism to either or both of the diastereomeric benz[a]anthracene 3,4-diol-1,2-epoxides, supports the bay region theory of polycyclic hydrocarbon carcinogenicity and provides the first example of a proximate carcinogenic metabolite that is much more active than the parent hydrocarbon on mouse skin.

Animals↗
PubMed1977

Epidermal hyperplasia after topical application of benzo (a) pyrene, benzo (a) pyrene diol epoxides, and other metabolites.

The effects of benzo(a)pyrene (BP) and 22 derivatives upon the number of nuclei per unit length of epidermis, the number of cell layers of epidermis, and the thickness of the epidermal layer were studied. Several derivatives of BP induced changes in epidermal morphology that are typical of those produced by various agents that promote skin tumorigenesis after application of an initiator. The most potent compounds tested were the BP diol epoxides, (+/-)-7beta,8alpha-dihydroxy-9beta, 10beta-epoxy-7,8,9,10-tetrahydrobenzo-(a)pyrene (diol epoxide 1) and (+/-)-7beta,8alpha-dihydroxy-9alpha, 10alpha-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene (diol epoxide 2). These derivatives were followed in activity by 9-hydroxybenzo(a)pyrene, 2-hydroxybenzo(a)pyrene, and by 9,10-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene. The possible implications of these results with regard to the carcinogenicity of BP on mouse skin are discussed.

Administration, Topical↗
PubMed1977

Marked differences in the tumor-initiating activity of optically pure (+)- and (-)-trans-7,8-dihydroxy-7,8-dihydrobenzo(a)pyrene on mouse skin.

The ability of optically pure (+)- and (-)-trans-7,8-dihydroxy-7,8-dihydrobenzo(a)pyrene to initiate skin tumors in mice was determined with a two-stage tumorigenesis system. A single application of 50 to 200 nmoles of (+)- or (-)-trans-7,8-dihydroxy-7,8-dihydrobenzo(a)pyrene to the backs of CD-1 mice followed by twice-weekly applications of 12-O-tetradecanoyl-phorbol-13-acetate revealed that the (-)-enantiomer was 5- to 10-fold more potent than was the (+)-enantiomer as a tumor initiator at the three dosage levels tested. When the tumor-initiating activities of the (+)0 and (-)-enantiomers of trans-7,8-dihydroxy-7,8-dihydrobenzo(a)pyrene were compared to the activity of benzo(a)pyrene at an equimolar dose, the (-)-enantiomer was more active while the (+)-enantiomer was considerably less active. This is the first report of differences in the carcinogenic activity between optical enantiomers.

Animals↗
PubMed1977

Carcinogenicity of benzo-ring derivatives of benzo(a)pyrene on mouse skin.

Benzo(a)pyrene (BP) and several benzo-ring derivatives of BP were tested for carcinogenic activity in mice by topical application of each compound once every 2 weeks for 60 weeks. Chronic treatment of C57BL/6J mice with (+/-)-trans-7,8-dihydroxy-7,8-dihydrobenzo(a)pyrene (0.025 to 0.10 micronmole/application) indicated that the dihydrodiol was slightly more active as a complete carcinogen than the parent hydrocarbon BP. 7,8-Dihydroxy-7,8,9,10-tetrahydro-benzo(a)pyrene, a compound related to (+/-)-trans-7,8-dihydroxy-7,8-dihydrobenzo(a)pyrene but which lacks the double bond at position 9,10, was inactive as a carcinogen on mouse skin. These results indicate the importance of the double bond at position 9,10 for the carcinogenic activity of (+/-)-trans-7,8-dihydroxy-7,8-dihydrobenzo(a)pyrene. Chronic treatment of mice with -.4 micronmole of the highly mutagenic (+/-)-7,beta,8alpha-dihydroxy-9alpha, 10alpha-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene, (+/-)-7beta,8alpha-dihydroxy-9beta, 10beta-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene, or 9,10-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene every 2 weeks for 60 weeks resulted in tumor incidences of 0, 8, and 4%, respectively, whereas BP at this dose caused a 100% tumor incidence. The high reactivity of the three epoxides may account for their inactivity or their weak carcinogenic activity on mouse skin.

Animals↗
PubMed1977

Comparison of the tumor-initiating activities of benzo(a)pyrene arene oxides and diol-epoxides.

The ability of arene oxides, and diol epoxides of benzo(a)pyrene to initiate skin tumors in mice was determined by using a two-stage system of tumorigenesis. (+/-)-7beta,8alpha-Dihydroxy-9alpha, 10alpha-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene was a more effective tumor initiator than was (+/-)-7beta,8alpha-dihydroxy-9beta,10beta-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene when applied topically to CD-1 mice and then followed by twice-weekly applications of the promotor 12-O-tetradecanoylphorbol-13-acetate. (+/-)-7beta,8alpha-Dihydroxy-9alpha,10alpha-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene was approximately 20 to 30% as active as benzo(a)pyrene was as a tumor initiator. (+/-)-7beta,8alpha-Dihydroxy-7beta,8beta-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene, benzo(a)pyrene, 9,10-oxide, and benzo(a)pyrene 11, 12-oxide, possessed about 1, 2, and 10%, respectively, of the tumor-initiating activity of benzo(a)pyrene.

Animals↗
PubMed1976

Metabolism of benzo(a)pyrene and benzo (a)pyrene derivatives to mutagenic products by highly purified hepatic microsomal enzymes.

A highly purified and reconstituted hepatic microsomal monooxygenase system, completely free of epoxide hydrase and consisting of cytochrome P-448 from 3-methylcholanthrene-treated rats, NADPH-cytochrome c reductase, phosphatidylcholine, and NADPH, metabolizes benzo (a)pyrene to products highly mutagenic in strains TA 98 and TA 1538 of Salmonella typhimurium. The formation of mutagenic metabolites is completely dependent on the presence of benzo (a)pyrene, NADPH, NADPH-cytochrome c reductase, and cytochrome P-448 and is partially dependent on phosphatidylcholine. Mutation frequency in both strains is linearly related to amount of cytochrome P-448 and to time of incubation. Highly purified cytochrome P-450 from phenobarbital-treated rats is relatively poor in catalyzing the formation of mutagenic metabolites from benzo (a)pyrene. Addition of 7.5 to 75 units of highly purified epoxide hydrase to the cytochrome P-448-dependent monooxygenase system decreases the number of mutations by approximately 50% and30% in strains TA 1538 and TA 98, respectively. Additional amounts of epoxide hydrase (300 units) fail to further suppress mutations, indicating that at least some, but probably not all, of the mutagenic metabolites of benzo (a)pyrene are arene oxides. In the absence of a monooxygenase system, mutations induced by benzo (a)pyrene 4,5-oxide are readily quenched by epoxide hydrase, whereas mutations induced by a diol epoxide metabolite of benzo (a)pyrene [(+/-)-7 beta, 8alpha-dihydroxy-9beta, 10beta-epoxy-7,8,9,10-tetrahydrobenzo (a)pyrene] are not. Several known and potential phenolic and dihydrodiol metabolites of benzo (a)pyrene are metabolized to products mutagenic in the Salmonella. The number of mutations induced per nmol of hemoprotein is approximately 3- to 4-fold higher when trans-7,8-dihydroxy-7,8-dihydrobenzo (a)pyrene replaces benzo (a)pyrene as a substrate for the cytochrome P-448-dependent monooxygenase system. Little or no mutagenic activity is observed with trans-dihydrodiols at positions 4,5, 9,10, or 11,12 of the hydrocarbon, either in the absence or presence of the active monooxygenase system. Of the 12 possible isomeric monophenols of benzo (a)-pyrene, only 6- and 12-hydroxybenzo (a)pyrene are moderately active bacterial mutagens; 1-, 2-, 3-, 6-, 9-, and 12-hydroxybenzo (a)pyrene are premutagens (i.e. metabolized to mutagenic products); and 4-, 5-, 7-, 8-, 10-, and 11-hydroxybenzo (a)pyrene have little or no mutagenic activity with or without further oxidative metabolism. Benzo (a)pyrene 7,8-oxide, a carcinogen on mouse skin, is weakly mutagenic but can be further metabolized to a highly active bacterial mutagen(s), presumably diol epoxide(s), by a combination of epoxide hydrase and the cytochrome P-448 monooxygenase system. This is the first example of a direct role of epoxide hydrase in the metabolic activation of a chemical to a toxic product.

Animals↗
PubMed1976

Multiple forms of rat liver cytochrome P-450. Immunochemical evidence with antibody against cytochrome P-448.

Purified hepatic cytochrome P-448 from 3-methylcholanthrene-treated rats was used to produce antibody in rabbits. The cytochrome P-448 antibody (IgG fraction) isolated from immune rabbit serum is quite specific and precipitates purified rat liver cytochrome P-448 at low antibody to protein ratios when assayed by the Ouchterlony double diffusion technique. Purified hepatic cytochrome P-450 from phenobarbital-treated rats cross-reacts poorly with the cytochrome P-448 antibody as do purified rabbit hepatic cytochrome P-448 and P-450. No cross-reaction is observed with purified cytochrome P-450 from beef adrenal mitochondria or from Pseudomonas putida in Ouchterlony double diffusion experiments. The cytochrome P-448 antibody produces a single distinct precipitin band with purified rat cytochrome P-448. In contrast, purified liver cytochrome P-450 from phenobarbital-treated rats gives three precipitin bands, all of which contain hemeprotein as judged by benzidine staining. At least two of the three precipitin bands are immunochemically different from the precipitin band formed with cytochrome P-448. When added to the reconstituted system, the cytochrome P-448 antibody inhibits purified rat cytochrome P-448- and P-450-supported N-demethylation of benzphetamine, O-deethylation of ethoxycoumarin, hydroxylation of benzo[a]pyrene, and the hydroxylation of testosterone at the 6beta, 7alpha, and 16alpha positions. Antibody inhibits cytochrome P-448-supported metabolism more than cytochrome P-450-supported metabolism except for benzo[a]pyrene hydroxylation at low antibody to hemeprotein ratios. In addition, the pattern and extent of inhibition of the cytochrome P-450 system depends on the substrate used, suggesting that multiple forms of the hemeprotein are present in the purified preparation from phenobarbital-treated rats. The observed patterns of immunoprecipitation and inhibition of catalytic activity indicate that (a) cytochrome P-448 from 3-methylcholanthrene-treated rats is immunochemically different from cytochrome P-450 from phenobarbital-treated rats, and (b) there appear to be at least three hemeprotein forms in the purified cytochrome P-450 preparation from phenobarbital-treated rats.

Animals↗