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W Levin

Publications and source records attributed to W Levin.

At least 253 records · Page 14Linked to original sources
PubMed1978

Tumorigenicity studies with diol-epoxides of benzo(a)pyrene which indicate that (+/-)-trans-7beta,8alpha-dihydroxy-9alpha,10alpha-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene is an ultimate carcinogen in newborn mice.

The tumorigenic activities of benzo(a)pyrene(BP), (+/-)-trans-7beta,8alpha-dihydroxy-9beta,10beta-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene (diol-epoxide 1), (+/-)-trans-7beta,8alpha-dihydroxy-9alpha,10alpha-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene (diol-epoxide 2), (+/-)-trans-7,8,-dihydroxy-7,8-dihydrobenzo(a)pyrene (BP 7,8-dihydrodiol), and the tetraols derived from the hydrolysis of diol-epoxide 2 were evaluated in newborn mice. The mice were given injections sequentially of 4, 8, and 16 nmoles of each compound on the first, eighth, and fifteenth days of life, and the animals were killed when they were 28 weeks old. Diol-epoxide 1 was highly toxic in newborn mice, and most of the animals treated with this compound died before weaning. Diol-epoxide 2 and BP 7,8-dihydrodiol were, respectively, about 40- and 15-fold more active than BP in causing pulmonary adenomas. Vehicle-treated control animals had an average of 0.13 lung adenoma/mouse, whereas animals treated with BP, BP 7,8-dihydrodiol, or diol-epoxide 2 had, respectively, 0.24, 1.77 and 4.42 pulmonary adenomas/mouse. Diol-epoxide 1 and the tetraols derived from diol-epoxide 2 did not induce pulmonary adenomas. The inactivity of diol-epoxide 1 under the conditions of our study should be interpreted with caution because of the high toxicity of this compound. The results of our study provide evidence that BP 7,8-dihydrodiol is a proximate carcinogenic metabolite and that diol-epoxide 2 is an ultimate carcinogenic metabolite of BP in the newborn mouse.

Adenoma↗
PubMed1978

Skin tumor-initiating activities of the twelve isomeric phenols of benzo(a)pyrene.

The skin tumor-initiating activities of the 12 isomeric phenols of benzo(a)pyrene (BP) were determined in mice by use of a two-stage system of tumorigenesis. 11-Hydroxybenzo(a)pyrene was moderately active, whereas 2-hydroxybenzo(a)pyrene and BP were strong tumor initiators when applied topically to CD-1 mice and followed by twice-weekly applications of the promoter 12-O-tetradecanoylphorbol-13-acetate. 1-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, and 12-hydroxybenzo(a)pyrene had less than 5% of the tumor-initiating activity of BP when the data were expressed as papillomas per mouse. After 30 weeks of promotion, the number of papillomas per mouse was 8.4, 8.5, and 2.8, respectively, for the animals treated with BP, 2-hydroxybenzo(a)pyrene, and 11-hydroxybenzo(a)pyrene. A 5-week latency period before the appearance of the first tumor was observed after the application of either 2-hydroxybenzo(a)pyrene or BP, whereas a slightly longer latency period of 7 weeks was observed following application of 11-hydroxybenzo(a)pyrene. The time required for 50% of the animals to develop tumors was 13 weeks for animals treated with BP and 15 weeks for animals treated with 2- or 11-hydroxybenzo(a)pyrene.

Animals↗
PubMed1978

Exceptional carcinogenic activity of benz[a]anthracene 3,4-dihydrodiol in the newborn mouse and the bay region theory.

Benz[a]anthracene and the five metabolically possible trans-dihydrodiols of benz[a]anthracene were tested for carcinogenicity in newborn Swiss-Webster mice. Four hundred, 800, and 1600 nmoles hydrocarbon i.p. were sequentially injected on Days 1, 8, and 15 of life. The mice were killed at 22 weeks of age. Of the mice treated with trans-3,4-dihydroxy-3, 4-dihydrobenz[a]anthracene, 24% developed malignant lymphoma, whereas 4% of the animals treated with benz[a]anthracene had malignant lymphoma. None of the animals treated with the trans-1,2-dihydroxy-1,2-dihydrobenz[a]anthracene, trans-5,6-dihydroxy-5,6-dihydrobenz[a]anthracene, trans-8,9-dihydroxy-8,9-dihydrobenz[a]anthracene, or trans-10,11-dihydroxy-10,11-dihydrobenz[a]anthracene had malignant lymphoma. trans-3,4-Dihydroxy-3,4-dihydrobenz[a]anthracene caused about 35-fold more pulmonary adenomas than did benz[a]anthracene, whereas the trans-1,2-dihydroxy-1,2-dihydrobenz[a]anthracene, trans-5,6-dihydroxy-5,6-dihydrobenz[a]anthracene, trans-8,9-dihydroxy-8,9-dihydrobenz[a]anthracene, and trans-10, 11-dihydroxy-10,11-dihydrobenz[a]anthracene had little or no activity. The exceptionally high carcinogenicity of trans-3,4-dihydroxy-3,4-dihydrobenz[a]anthracene is consistent with the metabolism of this compound to either or both of the diastereomeric bay region 3,4-dihydroxy-1,2-epoxy-1,2,3,4-tetrahydrobenz[a]anthracenes, and the data support the bay region theory of polycyclic hydrocarbon carcinogenesis.

Adenoma↗
PubMed1978

Evidence for bay region activation of chrysene 1,2-dihydrodiol to an ultimate carcinogen.

The tumor-initiating activities of chrysene and the three metabolically possible trans-dihydrodiols at the 1,2-, 3,4-, and 5,6-positions of chyrsene were determined on the skin of female CD-1 mice. A single topical application of 0.4, 1.25, or 4.0 mumol of each compound was followed 7 days later by twice-weekly applications of the tumor promoter 12-O-tetradecanoylphorbol-13-acetate for 25 weeks. The most potent tumor initiator was chrysene 1,2-dihydrodiol, which had approximately twice the tumorigenic activity of the parent hydrocarbon chrysene at all doses tested. Chrysene 3,4-dihydrodiol and chrysene 5,6-dihydrodiol had no significant tumorigenic activity. 1,2-Dihydroxy-1,2,3,4-tetrahydrochrysene, a compound related to chrysene 1,2-dihydrodiol but with the conjugated nonaromatic double bond removed from the 3,4-position of the molecule, had less than 25% of the tumorigenic activity of chrysene 1,2-dihydrodiol. These results indicate that chrysene 1,2-dihydrodiol is a proximate carcinogenic metabolite of chrysene and that a chrysene 1,2-diol-3,4-epoxide, in which the epoxide group forms part of the bay region in the molecule, is a likely candidate as an ultimate carcinogenic metabolite of chrysene.

Animals↗
PubMed1978

Marked differences in the carcinogenic activity of optically pure (+)- and (-)-trans-7,8-dihydroxy-7,8-dihydrobenzo(a)pyrene in newborn mice.

Optically pure (+)- and (-)-trans-7,8-dihydroxy-7,8-dihydrobenzo(a)pyrenes [(+)- and (-)-BP 7,8-dihydrodiol] were tested for carcinogenicity by giving newborn mice i.p. injections of 20, 40, and 80 nmol of compound on Days 1, 8, and 15 of life. The animals were killed at 17 weeks of age. Control mice had 0.10 pulmonary adenoma per mouse, whereas animals treated with (+)-BP 7,8-dihydrodiol and (-)-BP 7,8-dihydrodiol had 0.16 and 9.28 pulmonary adenomas per mouse, respectively. When a 5-fold higher dose was administered according to the above dosage schedule, (+)-dihydrodiol caused 2.34 pulmonary adenomas per mouse and (-)-BP 7,8-dihydrodiol caused 32.2 pulmonary adenomas per mouse. When 200, 400, and 800 nmol of benzo(a)pyrene or (+)-BP 7,8-dihydrodiol were administered sequentially on Days 1, 8, and 15 of life, 4.13 and 18.5 pulmonary adenomas per mouse, respectively, were observed when the mice were 17 weeks of age. This high dose of (-)-BP 7,8-dihydrodiol killed most of the mice. Administration of (-)-BP 7,8-dihydrodiol caused a high incidence of malignant lymphomas, whereas (+)-BP 7,8-dihydrodiol and benzo(a)pyrene had little or no ability to cause malignant lymphomas.

Adenoma↗
PubMed1977

The role of mastectomy in locally advanced breast cancer.

The role of mastectomy in locally advanced breast cancer remains to be established. Experience at the Breast Clinic at the Provincial Hospital, Port Elizabeth, strongly suggests that mastectomy improves local control. The addition of mastectomy to a basic regimen of radiotherapy and adjuvant chemotherapy now forms the basis of a prospective clinical trial.

Adult↗
PubMed1977

Liver microsomal epoxide hydrase.

1. The substrate specificity of membrane-bound and purified epoxide hydrase from rat liver microsomes has been studied. Both enzyme preparations catalyzed the hydration of a variety of alkene oxidase as well as arene oxides of several polycyclic aromatic hydrocarbons. 2. Unlike the membrane-bound enzyme, the rate of hydration for most of the substrates catalyzed by the purified epoxide hydrase was constant for only 1 or 2 min. The addition of dilauroyl phosphatidylcholine or heated microsomes to the incubation mixture extended the linearity of the reaction. 3. When rat liver microsomes were used as the source of the enzyme, the apparent Km values for many of the substrates were dependent on the amount of microsomes used. When purified epoxide hydrase was used as the enzyme source and benzo(a)pyrene 11,12-oxide as substrate, the apparent Km for benzo(a)pyrene 11,12-oxide was independent of enzyme concentration but dependent on added lipid concentration. Thus, in the absence of added dilauroyl phosphatidylcholine or in the presence of this lipid at a concentration below its critical micelle concentration, the observed Km for benzo(a)pyrene 11,12-oxide remained constant. However, when the lipid concentration was greater than the critical micelle concentration, the apparent Km value increased linearly with lipid concentration. These results are consistent with a model based on the partition of lipid-soluble substrate between the lipid micelle and the aqueous medium.

Animals↗
PubMed1977

Inhibition by CO of hepatic benzo[a]pyrene hydroxylation and its reversal by monochromatic light.

Inhibition by CO of benzo[a]pyrene hydroxylation was studied in hepatic microsomes from rats pretreated with phenobarbital, 3-methylcholanthrene or 2,3,7,8-tetrachlorodibenzo-p-dioxin, from animals treated with vehicle (saline or corn oil, respectively), and in a reconstituted microsomal cytochrome P-448 system prepared from rats treated with 3-methylcholanthrene. In all preparations the hydroxylation was inhibited by CO, and this inhibition was most effectively reversed by irradiation with monochromatic light of 450 nm wavelength. These observations provide direct evidence that the oxygen-activating component of all the examined benzo[a]pyrene hydroxylase systems is a P-450-type heme protein. The only striking difference observed in these systems was the low CO sensitivity of the benzo[a]pyrene hydroxylase reaction in microsomes from animals treated with 3-methylcholanthrene or 2,3,7,8-tetrachlorodibenzo-p-dioxin. Half-maximal inhibition occurred at CO/O2 ratios of 9--12, rather than at 1--2, which is the usual range for P-450-linked mixed-function oxidase reactions. In contrast, the reconstituted benzo[a]pyrene hydroxylase system, with purified cytochrome P-448 from 3-methylcholanthrene-induced rats, exhibited a considerably higher sensitivity towards CO (CO/O2 ratio approximately 1), well within the range for mixed-function oxidase reactions. It is concluded that the observed diminished CO sensitivity of microsomal benzo[a]pyrene hydroxylase in 3-methylcholanthrene- or 2,3,7,8-tetrachlorodibenzo-p-dioxin-treated rats results from alterations in the composition and/or structural organization of the microenvironment of cytochrome P-448 in the endoplasmic reticulum in response to the inducing action of polycyclic aromatic hydrocarbons and related agents, and is not related to changes in the heme protein P-448 per se. The detailed nature of these changes is the subject of ongoing studies.

Animals↗