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L W Wattenberg

Publications and source records attributed to L W Wattenberg.

At least 55 records · Page 3Linked to original sources
PubMed1985

Metabolism of 3-tert-butyl-4-hydroxyanisole to 3-tert-butyl-4,5-dihydroxyanisole by rat liver microsomes.

3-tert-Butylhydroxyanisole (3-BHA) is an antioxidant which can have a modulating effect on chemical carcinogenesis. Information concerning the metabolism of 3-BHA is incomplete. In the present study, the metabolites formed by incubating 3-BHA with liver microsomes from rats given beta-naphthoflavone by p.o. intubation were studied. Three metabolites were identified, two major metabolites and a minor metabolite. One of the major metabolites was the catechol of 3-BHA, i.e., 3-tert-butyl-4,5-dihydroxyanisole, which has not previously been reported. A characteristic of this compound is its capacity to be oxidized readily. The second major metabolite was tert-butyl hydroquinone which has been reported previously to be a liver microsomal metabolite of 3-BHA. The third metabolite, which occurred in small quantities, was 2,2'-dihydroxy-3,3'-di-tert-butyl-5,5'-dimethoxydiphenyl. 2,2'-Dihydroxy-3,3'-di-tert-butyl-5,5'-dimethoxydiphenyl has been identified previously as a major metabolite of 3-BHA in the rat intestine. An understanding of the metabolism of 3-BHA may assist in elucidating the mechanism(s) of its biological effects.

Animals↗
PubMed1984

Effects of cyclic 12-, 8-, and 6-carbon compounds on glutathione S-transferase activity.

The effects of feeding ICR/Ha mice cyclic 12-, 8-, and 6-carbon compounds on glutathione S-transferase (GST) activity in the liver, intestinal mucosa, and the forestomach were determined. The compounds used for this study were 1,5,9-trans,trans,cis- cyclododecatriene , 1,2-trans-5,6-trans-9,10-cis- cyclododecatriene -1,2-oxide, cyclododecanol , cyclododecene oxide, cyclododecane , 1,5- cyclooctadiene , cyclooctene oxide, cyclohexene, and cyclohexene oxide. The unsaturated cyclic 12-carbon compounds elicited the greatest increase in GST activity. Thus, feeding 1,5,9-trans,trans,cis- cyclododecatriene increased this activity almost 4-fold in the livers and the intestinal mucosa of experimental animals. Cyclic 8-carbon compounds were less effective and feeding the cyclic 6-carbon compounds did not result in any significant increase in GST activity. None of the compounds elicited increased GST activity in the fore-stomach. Previous studies have shown that compounds inducing increased GST activity can protect against chemical carcinogens. It remains to be determined whether the compounds identified in the present investigation as inducers of this enzyme system will have such protective capacities.

Animals↗
PubMed1984

Effect of brussels sprouts and cabbage on drug conjugation.

Ten healthy subjects were fed three diets for 10 days each: a control diet, a cabbage and brussels sprouts--containing diet, and the control diet a second time. Oxazepam was taken on day 7 and acetaminophen on day 10 of each dietary regimen. The test diet stimulated the metabolism of acetaminophen, at least in part by enhanced glucuronidation, as evidenced by a 16% decrease in mean plasma AUC, a 17% increase in mean metabolic clearance rate, an increased ratio of acetaminophen glucuronide to acetaminophen in plasma from 1 to 11 hr after drug and an 8% increase in mean 24-hr urinary recovery of acetaminophen glucuronide, which returned toward control when the subjects were fed the control diet a second time. There were no comparable changes in the metabolism of acetaminophen to acetaminophen sulfate. When the subjects ate the test diet, 24-hr urinary recovery of the cysteine conjugate and of 3-methoxyacetaminophen sulfate, end-products of minor oxidative pathways, the former involving a toxic intermediate, decreased 13% and 22%. Cabbage and brussels sprouts induced a 17% decrease in mean plasma AUC and a 19% increase in mean metabolic clearance rate for oxazepam, but there was no change in mean plasma t1/2 for this drug, nor was there a change in ratio in plasma of oxazepam glucuronide to oxazepam.

Acetaminophen↗
PubMed1983

Effects of p-methoxyphenol and diet on carcinogen-induced neoplasia of the mouse forestomach.

Previously, p-methoxyphenol fed in the diet was found to be the most potent inhibitor of benzo(a)pyrene-induced neoplasia of the mouse forestomach of 18 phenols investigated. In the present study, the effects of p-methoxyphenol on the direct-acting carcinogen, beta-propiolactone (BPL), were determined. p-Methoxyphenol administered at 1 or 4 hr prior to BPL or fed in the diet markedly inhibited BPL-induced neoplasia of the mouse forestomach. Of 10 phenols tested by p.o. intubation, it was the only one that exerted a significant inhibitory activity. Thus far, p-methoxyphenol appears to be an effective inhibitor only when given prior to carcinogen administration. During these studies, it was found that the nature of the diet markedly altered the neoplastic response of the mouse forestomach to BPL but not to benzo(a)pyrene.

Animals↗
PubMed1983

Inhibition of neoplasia by minor dietary constituents.

Food contains a large number of inhibitors of carcinogenesis, including phenols, indoles, aromatic isothiocyanates, methylated flavones, coumarins, plant sterols, selenium salts, protease inhibitors, ascorbic acid, tocopherols, retinol, and carotenes. The diversity and widespread occurrence of these compounds in food make it virtually impossible to consume a diet that does not contain inhibitors of carcinogenesis. Inhibitors can be classified as to the time in the carcinogenic process at which they act. Some prevent formation of carcinogens. Others, termed "blocking agents," prevent carcinogens from reaching or reacting with critical target sites. A third group called "suppressing agents" are effective when fed subsequent to administration of carcinogens. Some compounds inhibit at more than one time point. The major emphasis in this paper is on blocking agents, in particular those that act by enhancing host detoxification systems. Mary blocking agents produce a coordinated enhancement of multiple detoxification systems. Two distinctive patterns termed type A and type B have been identified. One enzyme system commonly induced by blocking agents is glutathione S-transferase. On the basis of this information, induction of glutathione S-transferase activity is being used to detect the presence of blocking agents in complex natural products. Green coffee beans induce increased glutathione S-transferase activity and inhibit mammary neoplasia in the rat resulting from administration of 7,12-dimethylbenz(a)anthracene. Two potent inducers of increased glutathione S-transferase activity have been isolated from green coffee beans. These are kahweol palmitate and cafestol palmitate. In recent work, several plant materials have been found to inhibit carcinogenesis when fed after carcinogen exposure. The identification and further investigation of inhibitors present in food are of importance so that their impact on the occurrence of neoplasia in humans can be ascertained.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1982

Glutathione S-transferase activity: enhancement by compounds inhibiting chemical carcinogenesis and by dietary constituents.

Benzyl isothiocyanate, beta-naphthoflavone, coumarin, alpha-angelicalactone, disulfiram, indole-3-carbinol and indole-3-acetonitrile induced increased glutathione (GSH) S-transferase activity in the liver and small intestine in female ICR/Ha mice. All seven compounds are inhibitors of chemical carcinogenesis. In additional work, several dietary constituents increased GSH S-transferase activity. Consumption of diets containing dried powdered preparations of brussels sprouts, cabbage, coffee beans, or tea leaves resulted in increased GSH S-transferase activity. Mice fed an unrefined diet (Purina Rat Chow) had a higher GSH S-transferase activity than those fed a semipurified diet. The results of the present study indicated that the composition of the diet can alter the activity of an important enzyme system having the capacity to detoxify chemical carcinogens.

Animals↗
PubMed1982

Isolation and identification of kahweol palmitate and cafestol palmitate as active constituents of green coffee beans that enhance glutathione S-transferase activity in the mouse.

Glutathione (GSH) S-transferase is a major detoxification enzyme system that catalyzes the binding of a variety of electrophiles, including reactive forms of chemical carcinogens, to GSH. Green coffee beans fed in the diet induced increased GSH S-transferase activity in the mucosa of the small intestine and in the liver of mice. A potent compound that induces increased GSH S-transferase activity was isolated from green coffee beans and identified as kahweol palmitate. The corresponding free alcohol, kahweol, and its synthetic monoacetate are also potent inducers of the activity of GSH S-transferase. A similar diterpene ester, cafestol palmitate, isolated from green coffee beans was active but less so than was kahweol palmitate. Likewise, the corresponding alcohol, cafestol, and its monoacetate showed moderate potency as inducers of increased GSH S-transferase activity. Kahweol palmitate and cafestol palmitate were extracted from green coffee beans into petroleum ether. The petroleum ether extract was fractionated by preparative normal-phase and reverse-phase liquid chromatographies successively. Final purification with silver nitrate-impregnated thin-layer chromatography yielded the pure palmitates of cafestol and kahweol. The structures were determined by examination of the spectroscopic data of the esters and their parent alcohols and by derivative comparison.

Animals↗
PubMed1982

Enhancement of glutathione S-transferase activity of the esophagus by phenols, lactones, and benzyl isothiocyanate.

The effects of feeding p-methoxyphenol, benzyl isothiocyanate, coumarin, alpha-angelicalactone, 2-tert-butyl-4-hydroxyanisole, and 3-tert-butyl-4-hydroxyanisole on the glutathione S-transferase activity and sulfhydryl levels of esophagus and small bowel mucosa of ICR/Ha mice have been investigated. p-Methoxyphenol, benzyl isothiocyanate, coumarin, and 2-tert-butyl-4-hydroxyanisole increased glutathione S-transferase activity of the esophagus by 68 to 135%, alpha-angelicalactone was less effective, and 3-tert-butyl-4-hydroxyanisole had only a small enhancing capacity. All six compounds increased the sulfhydryl levels of the esophagus. The ranking order and magnitude of the enhancing effects of the six compounds on glutathione S-transferase activity are similar for esophagus and forestomach (previously published) but differ from that of the small bowel mucosa. Since esophageal cancer is an important cause of cancer deaths in many parts of the world, information as to factors which can enhance protective systems of this organ may be of value.

Animals↗
PubMed1981

Enhancement of glutathione S-transferase activity of the mouse forestomach by inhibitors of Benzo[a]pyrene-induced neoplasia of the forestomach.

The effects of glutathione S-transferases (GST) activity and acid-soluble sulfhydryl levels of a number of compounds previously investigated for their capacity to inhibit benzo[a]pyrene (BP)-induced neoplasia of the mouse forestomach were determined. Five of the compounds studied increased the GST activity of the forestomach 78-182%. The five compounds were: p-methoxyphenol, 2-tert-butyl-4-hydroxyanisole, coumarin, alpha-angelicalactone, and benzyl isothiocyanate. With the exception of benzyl isothiocyanate. With the exception of benzyl isothiocyanate, these compounds also increased acid-soluble sulfhydryl levels, but to a lesser magnitude. All five chemicals inhibited BP-induced neoplasia of the forestomach. These data indicate that enhancement of the GST activity by an amount of about 75% or greater is associated with a reduced carcinogenic response of the forestomach to BP. The data also suggest that such enhancement might be used as a method of identifying compounds likely to inhibit BP and other carcinogens detoxified in a similar manner. Inasmuch as inhibition of the action of carcinogens may involve mechanisms other than detoxification by GST, the failure to increase GST activity substantially does not rule out the possibility of a compound being an inhibitor.

Animals↗
PubMed1981

Inhibition of carcinogen-induced neoplasia by sodium cyanate, tert-butyl isocyanate, and benzyl isothiocyanate administered subsequent to carcinogen exposure.

The effects of sodium cyanate, tert-butyl isocyanate, and benzyl isothiocyanate on carcinogen-induced neoplasia were studied in experiments in which the test compound was fed starting 1 week following completion of carcinogen administrations. Under these conditions, all three test compounds exerted an inhibitory effect on the occurrence of 7,12-dimethylbenz(a)anthracene-induced neoplasia of the breast of Sprague-Dawley rats. In a second experiment model, sodium cyanate inhibited the occurrence of 1,2-dimethylhydrazine-induced neoplasia of the large bowel of female CF-1 mice. Thus, a new group of compounds has been identified which has inhibitory capacities against neoplasia when given subsequent to carcinogen exposure.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1981

Effects of 2- and 3-tert-butyl-4-hydroxyanisole on glutathione S-transferase and epoxide hydrolase activities and sulfhydryl levels in liver and forestomach of mice.

Butylated hydroxyanisole, a food additive, has been found to inhibit the neoplastic effects of a wide variety of chemical carcinogens. The commercially available preparations of butylated hydroxyanisole contain two isomers, 2-tert-butyl-4-hydroxyanisole (2-BHA) and 3-tert-butyl-4-hydroxyanisole (3-BHA). Both isomers induce increased activities of glutathione (GSH) S-transferase and epoxide hydrolase and increase acid-soluble sulfhydryl concentration in hepatic and forestomach tissues of A/HeJ mice. The inductions were assayed after 2 weeks of feeding diets containing the two isomers. 3-BHA induced an increase in the activity of hepatic microsomal epoxide hydrolase by 1.4 times that of the control. The activity of cytosolic GSH S-transferase was enhanced by both isomers. In the liver, the 3-BHA induction was more than 3 times higher than that of 2-BHA. In the forestomach, however, the induction effect of the two isomers was reversed. The overall magnitude of the induction was much lower in the forestomach than in the liver. Synergistic effects on the induction of GSH-S-transferase activity were observed in the forestomach cytosol when mixtures of different proportions of the two isomers were added to the diet. Maximum enzyme activity was obtained at a ratio of 75% 2-BHA and 25% 3-BHA. No synergistic effect was observed with the corresponding hepatic cytosolic enzyme. The relative inductive effects of 2- and 3-BHA on the acid-soluble sulfhydryl level of liver and forestomach tissues followed closely those on GSH S-transferase activity. The results of the present study show that the two isomers of butylated hydroxyanisole differ in the magnitude of their effects on carcinogen-metabolizing systems of the liver and forestomach.

Animals↗
PubMed1980

Inhibition of polycyclic aromatic hydrocarbon-induced neoplasia by sodium cyanate.

The effects of sodium cyanate on the occurrence of 7,12-dimethylbenz(a)anthracene- and benzo(a)pyrene-induced neoplasia have been studied in rodents. Sodium cyanate added to the diet for 8 days prior to challenge with 7,12-dimethylbenz(a)anthracene inhibits 7,12-dimethylbenz(a)anthracene-induced mammary neoplasia in female Sprague-Dawley rats. Likewise, sodium cyanate in the diet inhibits the occurrence of benzo(a)pyrene-induced neoplasia of the forestomach and lung of ICR/Ha mice. Inhibition of benzo(a)pyrene-induced pulmonary neoplasia in A/J mice also is brought about by this compound. The identification of sodium cyanate as an inhibitor of chemical carcinogenesis adds a new chemical structure to those found previously to have inhibitory properties.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1980

Inhibitors of chemical carcinogens.

A diverse group of compounds inhibit the action of chemical carcinogens when administered prior to and/or simultaneously with the carcinogen. The inhibitors include naturally-occurring constituents of foods as well as synthetic compounds introduced into the environment. Three general mechanisms of inhibition exist. The first, illustrated by disulfiram inhibition of dimethylhydrazine-induced neoplasia of the large bowel, is the direct blocking of enzymatic activation of the carcinogen to its reactive ultimate carcinogenic form. The second mechanism of inhibition entails the stimulation of a coordinated detoxification response which results in increased activity of detoxifying enzymes in the microsomes and also the cytosol. At least two subdivisions of this response occur. One, for which butylated hydroxyanisole is a prototype, shows enhanced activity of some microsomal enzymes but not aryl hydrocarbon hydroxylase (AHH). However, it does have a rapidly active component which results in marked alteration of microsomal metabolism of benzo(a)pyrene. Another, for which a prototypical inhibitor is beta-naphthoflavone is characterized by induction of increased AHH activity. The third general mechanism of carcinogen inhibition entails the direct scavenging of reactive carcinogenic species by the inhibitor. Evidence supporting the psosibility that inhibitors play a role in the response of humans to carcinogens consists of three types. The first is the chemical diversity of the inhibitors and their actual occurrence in the environment. The second is the resposiveness of the detoxification systems, particularly those in the tissues of the major portals of entry, to the naturally-occurring or synthetic inhibitors. The third is a group of epidemiological studies which suggest that individuals consuming relatively large quantities of vegetables, a major source of naturally-occurring inhibitors, are at lower risk from gastrointestinal cancers.

Animals↗
PubMed1980

Inhibitory effects of phenolic compounds on benzo(a)pyrene-induced neoplasia.

The inhibitory effects of 18 synthetic phenolic compounds added to the diet on benzo(a)pyrene-induced neoplasia of the forestomach of female ICR/Ha mice have been determined. Seven of the compounds showed suppression of neoplasia. The most potent inhibitors were p-methoxyphenol, 2-tert-butyl-4-hydroxyanisole [the minor isomer of 2(3)-tert-butyl-4-hydroxyanisole] and 3,5-di-tert-butylcatechol. A second group of compounds with a weaker inhibitory activity consisted of 3,5-di-tert-butylphenol, 3-tert-butyl-4-hydroxyanisole [the major isomer of 2(3)-tert-butyl-4-hydroxyanisole], 2-tert-butylhydroquinone, and 2-tert-butylphenol. In additional experiments, three naturally occurring phenolic derivatives of cinnamic acid, i.e., o-hydroxycinnamic acid, 3,4-dihydroxycinnamic acid (caffeic acid), and 4-hydroxy-3-methyoxycinnamic acid (ferulic acid), were investigated. All three suppressed benzo(a)pyrene-induced neoplasia of the forestomach. Humans ingest a variety of phenols. Data as to the inhibitory capacities of members of this group of compounds are of importance for evaluating the role that they play in determining the reaction to exposure to chemical carcinogens.

Animals↗
PubMed1979

Synthesis and chemical carcinogen inhibitory activity of 2-tert-butyl-4-hydroxyanisole.

The title compound 1 was selectively synthesized in its pure isomeric form by means of the hydroxyl-protecting reagent dimethyl-tert-butylchlorosilane. Exclusive silylation occurred at the less hindered hydroxyl group of 3. Dimethyl sulfate methylation of 4 gave 5 in excellent yield. Compound 1 was then obtained by acid hydrolysis of 5. The two BHA isomers, 1 and 2, were tested on their inhibitory effects toward benzo[alpha]pyrene-induced neoplasia in the forestomach of the ICR/Ha mouse. Both isomers, when added to the diet, reduced the number of mice with tumors and the number of tumors per mouse. Isomer 1, which has the less hindered free hydroxyl group, showed higher inhibitory effect in the present experimental model.

Animals↗