Lee W. Wattenberg

Inhibitors of Chemical Carcinogenesis

Publisher Summary Chemical carcinogens play a very significant role in the etiology of cancer in man. This chapter describes a number of compounds that have the capacity to inhibit the neoplastic effects of chemical carcinogens when administered either prior to exposure to the carcinogen or at the same time. The carcinogens have a common reactive form—namely, a positively charged electrophilic species that binds to macromolecules. Most of the inhibitors are synthetic compounds and exhibit great diversity of chemical structures. The chapter emphasizes on two groups of inhibitors that have relatively low toxicity. The first group includes antioxidants and some related compounds. These were initially selected for investigation because of the possibility that they can have a scavenging effect on reactive carcinogenic species. This group of inhibitors exerts an inhibitory effect when administered shortly before the carcinogen around 2-4 hours. The second group includes compounds that have as a common property the capacity to alter the activity of the microsomal mixed-function oxidase system. Most of these compounds induce an increase in mixed function oxidase activity and have a maximum effectiveness when administered 24 -48 hours prior to challenge by the carcinogen. The chapter also discusses test systems used for studying the inhibitors of chemical carcinogenesis and outlines their mechanism of action.

MICROSCOPIC HISTOCHEMICAL DEMONSTRATION OF STEROID-3β-OL DEHYDROGENASE IN TISSUE SECTIONS

A procedure for the microscopic histochemical demonstration of steroid-3β-ol dehydrogenase has been described. In agreement with reported quantitative biochemical data, positive reactions have been obtained in the adrenal cortex, corpus luteum, placenta, and interstitial cells of the testis. In addition, a strongly positive reaction is obtained in the interstitial cells of the rodent ovary.

EFFECTS OF COENZYME Q10 AND MENADIONE ON SUCCINIC DEHYDROGENASE ACTIVITY AS MEASURED BY TETRAZOLIUM SALT REDUCTION

Coenzyme Q10 and menadione have been shown to enhance the succinic dehydrogenase activity of rat liver homogenates and frozen sections as measured quantitatively by the reduction of INT. Increased formazan deposition as estimated by visual examination was also found in sections of liver and other tissues in comparable experiments with the two quinones in which the tetrazolium salt Nitro-BT was employed. Extraction of sections with acetone decreased the succinic dehydrogenase activity of liver sections by approximately two-thirds of that present in nonextracted sections as measured by INT reduction. The addition of coenzyme Q10 or menadione restored the activity to essentially that present in nonextracted sections incubated in the presence of the same constituents. These data suggest that a quinone, presumably coenzyme Q10, acts as an intermediate electron transport agent between succinic dehydrogenase and INT or Nitro-BT. The effects of coenzyme Q10 and menadione on the activities of diphosphopyridine nucleotide (DPNH) diaphorase, triphosphopyridine nucleotide (TPNH) diaphorase, α-glycerophosphate dehydrogenase and monoamine oxidase, all of which are demonstrable by tetrazolium salt reduction procedures, have been studied. Two of these enzymes, TPNH diaphorase and monoamine oxidase, show no significant enhancement of activity in the presence of coenzyme Q10, and a relatively slight enhancement in the presence of menadione. α-Glycerophosphate dehydrogenase shows a pattern of enhancement comparable to that of succinic dehydrogenase. DPNH diaphorase activity, while enhanced by both of the quinones, shows a lesser degree than is found with the succinic dehydrogenase and α-glycerophosphate dehydrogenase systems. The diverse effects of coenzyme Q10 and menadione on the five enzyme systems investigated in the present work indicate that the two quinones do not simply act as nonspecific intermediate electron carriers between dehydrogenase system and tetrazolium salt, but that they enhance enzyme activity by a more specific interaction with some component of the enzyme system.

HISTOCHEMICAL DEMONSTRATION OF REDUCED PYRIDINE NUCLEOTIDE DEPENDENT POLYCYCLIC HYDROCARBON METABOLIZING SYSTEMS

1. Histochemical procedures have been developed for the demonstration of reduced pyridine nucleotide dependent systems metabolizing 3, 4-benzypyrene, perylene, 9,10-dimethyl-1,2-benzanthracene and 1, 2-benzanthracene. 2. For these procedures, an in situ indicator technique has been employed in which alterations of the fluorescence of the substrates coated on tissue sections is used to demonstrate the sites of enzyme activity. 3. Positive reactions have been found in the hepatic cells of rat, mouse, hamster, monkey, and man. The cells of the central portion of the hepatic lobule are more active than those of the periphery in all species. 4. A survey of rat tissues has shown positive reactions also in the distal portion of the proximal convoluted tubules of the kidney, the zona fasciculata and zona reticularis of the adrenal, the interstitial cells of the testis, the follicular epithelium of the thyroid and the alveolar walls of the lung. 5. The activity is considerably higher in sections of liver, kidney, thyroid, testis, and lung from rats injected with methylcholanthrene than in control animals; in the adrenal, no such increase is found.

Studies of polycyclic hydrocarbon hydroxylases of the intestine possibly related to cancer: Effect of diet on benzpyrene hydroxylase activity

The effect of dietary manipulation on the benzpyrene hydroxylase activity of the small intestine of the rat has been investigated. Most, and possibly all, of the benzpyrene hydroxylase activity in this site is due to exogenous inducers in the diet. Rats fed a balanced purified diet or starved for one day or more show virtually no activity. A beginning survey of dietary constituents has revealed that a number of vegetables, particularly those belonging to the Brassicaceae family, contain inducers. Data indicate that diet could be of importance in determining the response of organisms to exposures to poly cyclic hydrocarbon carcinogens.

An Overview of Chemoprevention: Current Status and Future Prospects

Abstract The optimal way of dealing with any disease is by prevention. This is particularly true of cancer, with all of its complexities. A major problem that exists for cancer prevention is that we do not know the cause of over 50% of cancers. Even when causes are known, serious difficulties often exist in removing them. To the extent that causality cannot be dealt with effectively, other strategies merit consideration. One is chemoprevention. A great strength of chemoprevention is that a large number of compounds can prevent the occurrence of cancer, and a variety of mechanisms exist for producing such protection. Much of this review deals with efficacy, toxicity, and mechanisms of action of chemopreventive agents. Gap areas in information are discussed, as well as opportunities for producing compounds with optimal attributes. Chemoprevention is not simple, and successes may not come quickly. However, for both the general population and, even more urgently, for individuals at high risk, chemoprevention has the potential of providing an important means for cancer prevention.

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 t½ for this drug, nor was there a change in ratio in plasma of oxazepam glucuronide to oxazepam.

Effects of allyl methyl trisulfide on glutathione S-transferase activity and BP-induced neoplasia in the mouse.

Allyl methyl trisulfide (AMT), a constituent of garlic oil, was studied for its effects on glutathione S-transferase (GST) activity and on benzo[a]pyrene (BP)-induced neoplasia of the forestomach and lungs of female A/J mice. AMT induced increased GST activity in the forestomach, small bowel mucosa, liver, and lung. The forestomach and small bowel mucosa responded to a single low dose of AMT (3.0 mumol) given by oral intubation, whereas liver and lung were less reactive. A dose schedule of two administrations of 15 mumol AMT given 48 hours apart gave close-to-maximum induction in all four tissues and was chosen for investigation of its inhibitory effects. With this dose schedule, AMT produced an inhibition of BP-induced neoplasia of the forestomach as shown by a greater than 70% reduction in the number of tumors found at the completion of the experiment. Inhibition of pulmonary neoplasia did not occur. AMT is a member of a new class of naturally occurring chemicals that have the capacity to inhibit chemical carcinogenesis.

Nutrients and pancreatic cancer: a population-based case-control study

A case-control study was conducted in the Minneapolis-St Paul (Minnesota, United States) area to assess the role of dietary factors in the etiology of pancreatic cancer. Cases were White males aged 40 to 84 whose death certificate listed pancreatic cancer (exocrine only). White male controls were ascertained through random-digit dialing. Family members were interviewed about the subjects dietary usage in the two years prior to death (cases, n=212) or prior to interview (controls, n=220). Energy-adjusted,nutrient-intake, risk estimates were calculated. Among all respondents, negative trends were observed for polyunsaturated fat, linoleic acid, vitamin C, and β-carotene. Positive trends were observed for riboflavin and retinol. Point estimates were, in general, comparable between the analyses of all respondents and spouse-only respondents. The nutrients associated with a decreased risk for pancreatic cancer occur primarily in vegetables and fruits, of which the consumption of cruciferous and β-carotene-rich vegetables and citrus fruits provided the greatest reduction in risk.

Effects of disulfiram and related compounds on the metabolism in vivo of the colon carcinogen, 1,2-dimethylhydrazine

Abstract In view of the recent discovery that disulfiram (DF) and diethyldithiocarbamate (DDTC) inhibit the colon carcinogenicity of 1,2-dimethylhydrazine, a study of the effects of DF, DDTC, and the related compounds bis(ethylxanthogen) (BEX), carbon disulfide (CS2), sec-butyldisulfide (SBDS), diethylamine (DEA) and triethylamine (TEA) on the metabolism of 1,2-dimethylhydrazine-[14C] was undertaken. With respect to vehicle-treated control rats, DF, BEX, DDTC and CS2 significantly increased the levels of the 1,2-dimethylhydrazine metabolite azomethane and decreased the levels of 14CO2 in the exhaled air. These compounds significantly decreased the levels of urinary azoxymethane and methylazoxymethanol and also decreased the levels of 14C in various rat organs. DEA, TEA and SBDS were ineffective in all these respects. It is concluded that DF, BEX, DDTC and CS2 inhibit the N-oxidation in vivo of azomethane to azoxymethane, an essential step in the metabolic activation of 1,2-dimethylhydrazine. It appears likely that the effective agent in the inhibition of the N-oxidation of axomethane by DF. BEX and DDTC is CS2, a metabolic product of these compounds.