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L K Lam

Publications and source records attributed to L K Lam.

At least 55 records · Page 3Linked to original sources
PubMed1989

Inhibition of benzo[a]pyrene-induced forestomach neoplasia in mice by citrus limonoids.

The limonoids, limonin and nomilin, are bitter principles found in common edible citrus fruits. Nomilin, when given three times (at 5 and 10 mg per animal) every two days, induced increased glutathione S-transferase activity 2.48 and 3.44 times over the control, respectively, in the liver of female ICR/Ha mice. The increases of GST activity in the small intestinal mucosa were 3.00 and 4.17, respectively, over the control. Limonin, when given at the same dose levels, was not active in the liver. However, marginal activity was obtained in the small intestinal mucosa. Nomilin, which is the more active enzyme inducer, was found to inhibit benzo[a]pyrene (BP)-induced neoplasia in the forestomach of ICR/Ha mice. The number of mice with tumors was reduced from 100 to 72%, and the number of tumors per mouse was significantly decreased as a result of nomilin treatment. Limonin, which is a weak enzyme inducer, was less potent as an inhibitor of BP-induced neoplasia. These findings suggest limonoids as a class of regularly consumed natural products may be effective chemopreventive agents.

Animals↗
PubMed1989

The effect of citrus limonoids on hamster buccal pouch carcinogenesis.

Two citrus limonoids, limonin and nomilin, were tested for their effects on the development of 7,12-dimethylbenz[a]anthracene (DMBA)-induced buccal pouch epidermoid carcinomas. Forty-five female Syrian hamsters were divided into three equal groups. The left buccal pouches of the animals in each group were pretreated topically with two applications of dimethylsulfoxide (DMSO) (group I), a 2.5% solution of limonin dissolved in DMSO (group II) or a 2.5% solution of nomilin dissolved in DMSO (group III). After this initial treatment, 11 hamsters from each group were selected. The left buccal pouches of these animals were painted 2 or 3 times weekly with a 0.5% solution of DMBA in mineral oil. On alternate days the pouches were painted with DMSO (I), the 2.5% solution of limonin (II) or the 2.5% solution of nomilin (III). The 12 remaining hamsters were used as controls and were painted with mineral oil and DMSO (I), mineral oil and the 2.5% solution of limonin (II), or mineral oil and the 2.5% solution of nomilin (III). After 15 weeks the hamsters were killed, the pouches were excised and the tumors were counted and measured. Tumors of variable size were common in the animals treated with DMBA. However, the animals receiving topical applications of limonin exhibited a 60% reduction in tumor burden. Further comparisons between groups I and II showed that this reduction in tumor burden was due to a 20% decrease in tumor number and a 50% decrease in tumor mass. The results for group III showed that nomilin was considerably less effective as an inhibitor of DMBA-induced neoplasia.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1988

Analogs of diaminopimelic acid as inhibitors of meso-diaminopimelate dehydrogenase and LL-diaminopimelate epimerase.

Analogs 1-8 of diaminopimelic acid (DAP) were synthesized and tested for inhibition of purified meso-DAP D-dehydrogenase from Bacillus sphaericus and of LL-DAP epimerase from Escherichia coli. The dehydrogenase was assayed by monitoring NADPH formation spectrophotometrically at 340 nm. N-Hydroxy DAP 4, N-amino DAP 5, and 4-methylene DAP 6 are substrates of the dehydrogenase with relative rates exceeding those of the meso isomers of the thia analogs 1ab, 2ab, and 3ab. DAP epimerase was assayed by coupling the epimerization of LL-DAP to DL-DAP (Km = 0.26 mM) with the dehydrogenase-catalyzed oxidation of DL-DAP by NADP. Lanthionine isomers 1ab and 1c were stronger inhibitors of the epimerase (Ki = 0.18 mM, Ki' = 0.67 mM, and Ki = 0.42 mM, respectively) than the corresponding meso-sulfoxide 2ab or the meso-sulfone 3ab. Other isomers of 2 and 3, as well as compounds 7 and 8, showed no epimerase inhibition. N-Hydroxy DAP 4 was the most potent competitive inhibitor (Ki = 0.0056 mM) of the epimerase, whereas N-amino DAP 5 is weaker (Ki = 2.9 mM) and 4-methylene DAP 6 is a noncompetitive inhibitor (Ki' = 0.95 mM). Although none of the analogs tested showed time-dependent inactivation of either enzyme, compounds 4, 5, 6, and 7 display substantial antibacterial activities. Possible mechanisms of epimerase inhibition and significance of the DAP pathway as a target for antibiotics are discussed.

Amino Acid Isomerases↗
PubMed1988

Effects of butylated hydroxyanisole on glutathione S-transferase and catechol O-methyltransferase activities in Syrian golden hamsters.

The effects of dietary butylated hydroxyanisole (BHA) on the enzyme activities of glutathione (GSH) S-transferase and catechol O-methyltransferase (COMT) in the forestomach, small intestinal mucosa, and liver of Syrian golden hamsters and ICR/Ha mice were examined. GSH S-transferase activity in the hamster tissues was not enhanced appreciably after 1 or 4 weeks of feeding diets containing various concentrations of BHA. In general, short term (1 week) feeding of diets containing BHA did not differ from longer term (4 weeks) feeding of the same diets. In the forestomach of hamsters, a positive dose response on the activity of GSH S-transferase was obtained with increasing concentration of BHA in the diet for 1 or 4 weeks. The maximum effect of dietary BHA in hamsters was observed in the forestomach after 1 week of feeding, which induced an increase in GSH S-transferase activity to twice that of the control level. The same induction effect, however, was not apparent in the liver or in the small intestinal mucosa. Dietary BHA, at all concentrations studied, did not elicit any significant change in the activity of the GSH S-transferase enzyme in these two tissues. While the increase of enzyme activity in the forestomach of ICR/Ha mice was similar to that observed in the forestomach of hamsters, the induction of GSH S-transferase activity in the liver and in the small intestinal mucosa of the two animal species was drastically different. In contrast to the lack of response to dietary BHA in the hamster tissues, the induction of increased enzyme activity in the liver and intestinal mucosa of ICR/Ha mice, after 1 week of 2% BHA feeding, was greater than 7 and 11 times that of control respectively. The ineffectiveness of BHA as an enzyme inducer in the hamster tissues was similar for the activity of COMT. The enzyme activity in all three hamster tissues examined did not change significantly as a result of BHA incorporation into the diet for 1 week. In contrast, the COMT activity in the forestomach and small intestinal mucosa of the mouse was increased with increasing concentration of dietary BHA. At 2% BHA, the enzyme activity in the two tissues was 3 and 2 times that of the control level, respectively, whereas the enzyme activity in the liver remained at control level. These findings suggest that the overall unresponsiveness of detoxifying enzyme systems in the Syrian golden hamsters may be critical in the formation of forestomach tumors caused by BHA.

Animals↗
PubMed1988

Evaluation of the cytotoxic potential of catechols and quinones structurally related to butylated hydroxyanisole.

The cytotoxicity of 2- and 3-butylated hydroxyanisole (BHA) and 18 related aromatic compounds has been determined employing cultured P388 and KB cells. The phenolic compounds, 3-BHA and 2-BHA, had moderately low cytotoxic activity. Their corresponding catechols had ED50 values that were much lower than those of the parent compounds. This substantial increase in the cytotoxic activity is attributed to the presence of the catechol group, which is known to undergo one-electron oxidation readily to give the corresponding semiquinone radical. Other related catechols had similar cytotoxic activity. In general, derivatization of the catechol functionality resulted in a decrease of the cytotoxic potential of the compounds. Monoacetylation or monomethylation of the catechols gave products that were less potent cytotoxic agents than the parent compounds. Further loss of activity was observed when both hydroxy groups of the catechol function were blocked. Substitution of a methoxy group in place of a hydrogen atom in these compounds resulted in a significant increase of cytotoxicity, whereas the replacement of a methoxy group with a methyl group reduced the cytotoxicity. The catechols and quinones derived from 2-BHA were more active when compared with those derived from 3-BHA. The t-butyl group adjacent to the catechol or quinone moiety in the 3-BHA derivatives appeared to exert a significant steric effect toward the cytotoxic potential of these compounds. These results suggest the potential use of o-quinones and catechols as cytotoxic and antitumor agents.

Butylated Hydroxyanisole↗
PubMed1988

Differential tumorigenicity of 2(3)-tert-butyl-4-hydroxyanisole in the forestomach of Lakeview and Misaki Syrian golden hamsters.

The phenolic oxidant 2(3)-tert-butyl-4-hydroxyanisole (BHA), has been found to induce carcinogenic response in the forestomach of Syrian golden hamsters and other rodent species. In this study, the differential effects of BHA was determined in the forestomach of Syrian golden hamsters from different sources. Lakeview (LVG) Syrian golden hamsters were fed diets containing 2% BHA incorporating into semipurified, Purina and Oriental M diets for 30 weeks. No papilloma or severe hyperplasia was found in any of the experimental or control groups. A significant increase in the number of hamsters having mild hyperkeratosis and mild hyperplasia was found in the semipurified-BHA group. In contrast, greater than 82 and 90% of the Misaki hamsters developed moderate to severe hyperplasia, and 64 and 80% had papilloma in the forestomach of the 1 and 2% BHA groups respectively. The control group had one animal with moderate hyperplasia that was confined to the limiting ridge. The obvious difference in the appearance of the two strains of hamsters is their body weight. The Misaki hamsters were 20-30% heavier than the LVG hamsters from the beginning and toward the end of the experiment. These results showed that the diet alone was not the reason for the failure of BHA to induce forestomach papilloma in the LVG hamsters. A much longer latent period may be required for the LVG hamsters to develop neoplastic lesions in the forestomach. The high sensitivity of the Misaki hamsters provides a valuable tool to study weak nongenotoxic carcinogens.

Animals↗
PubMed1987

Effects of derivatives of kahweol and cafestol on the activity of glutathione S-transferase in mice.

The coffee constituents cafestol and kahweol are inducers of the activity of the detoxifying enzyme, glutathione S-transferase in laboratory animals. The two active functional groups, furan and glycol, on opposite ends of the diterpene nucleus of these two compounds have been modified. The resulting derivatives were evaluated for their ability to induce glutathione S-transferase activity in different tissues of the ICR/Ha mice. Derivatives of both cafestol and kahweol, which were the products of the modifications on the glycol function, retained much of the inducing properties of the parent compounds in the liver and mucosa of the small bowel. The effects of these compounds on the tissue acid-soluble sulfhydryl level, in general, were similar to those of the parent compounds. Some derivatives of kahweol, however, appeared to have lost their ability to induce increased levels of sulfhydryls in the liver. Catalytic hydrogenation of the furan moiety gave two products, the dihydro and tetrahydro derivatives. Both compounds and their corresponding acetates lost their effectiveness as inducers of glutathione S-transferase activity. In contrast, these compounds still retained their ability to induce increased levels of acid-soluble sulfhydryls in both the liver and the mucosa of the small bowel. These findings indicate that the furan moiety of cafestol and kahweol is vital to their biological activity as inducers of increased glutathione S-transferase activity.

Animals↗
PubMed1986

Characterization of bacterial mutagenicity mediated by 13-hydroxy-ent-kaurenoic acid (steviol) and several structurally-related derivatives and evaluation of potential to induce glutathione S-transferase in mice.

Stevioside is a sweet-tasting diterpene glycoside that is derived from Stevia rebaudiana (Bertoni) Bertoni (Compositae). It is used commercially in Japan and other parts of the world as a sucrose substitute. Whereas stevioside demonstrates no mutagenic activity in a variety of test systems, the aglycone, steviol (13-hydroxy-ent-kaurenoic acid), is mutagenic toward Salmonella typhimurium strain TM677 in the presence of a metabolic activating system derived from the liver of Aroclor 1254-pretreated rats. The required activating component is localized in the microsomal fraction of rat liver, suggestive of a cytochrome P-450-mediated reaction. Partially purified epoxide hydrolase does not inhibit steviol-induced mutagenicity, indicating that an active metabolite is not an epoxide that serves as a substrate for this enzyme preparation. The 13-hydroxy group of steviol is required for the expression of mutagenicity since ent-kaurenoic acid is nonmutagenic, and acetylation of steviol at this position negates mutagenicity. Similarly, diterpenes bearing a strong structural resemblance to steviol, cafestol and kahweol, were found to demonstrate no mutagenic activity toward Salmonella typhimurium TM677, as were their respective acetates and palmitic acid esters. Conversely, 19-O-beta-D-glucopyranosyl steviol, a potential hydrolysis product of stevioside, is mutagenic and bactericidal in the presence of a metabolic activating system. Additionally, in contrast to the nonmutagenic diterpenes cafestol and kahweol that are effective as inducers of glutathione S-transferase activity, evaluation by administration to mice proved steviol, isosteviol and various steviol glycosides to be inactive in this process. Thus, structural differences among these naturally occurring and semi-synthetic diterpenes appear to impart major differences in biological activity that may relate to human health upon dietary ingestion.

Animals↗
PubMed1986

Tomographic thallium-201 stress scintigraphy in the evaluation of coronary artery disease.

57 patients with chest pain, had tomographic thallium-201 stress scintigraphy (TTSS), and coronary angiography within three months of the TTSS. The exercise images were compared with delayed images obtained at 3 hours post-exercise. The sensitivity and specificity of locating individual coronary artery disease was 88% and 100% for disease of left anterior descending artery (LAD), 89% and 83% for right coronary artery disease (RCA), and 24% and 96% for left circumflex artery (LCX) disease. Other than for LCX disease, our results compare favourably with other reports. The overall accuracies are 91%, 86% and 60% for LAD, RCA and LCX disease respectively.

Angina Pectoris↗
PubMed1985

Inhibition of carcinogenesis by some minor dietary constituents.

Previous work has shown that food contains a large number of minor dietary constituents that can inhibit the occurrence of cancer. Additional inhibitors from four different natural sources will be the subject of this presentation. 1. Citrus fruit oils. Orange, tangerine, lemon, and grapefruit oils given p.o. induce increased glutathione (GSH) S-transferase activity in tissues of the mouse. When fed in the diet prior to and during the course of administration of benzo(a)pyrene (BP), the four citrus fruit oils inhibit formation of tumors of both the forestomach and lungs of mice. When fed either before or after the administration of 7,12-dimethylbenz(a)anthracene (DMBA) orange oil inhibits mammary tumor formation. 2. Garlic oil. Allyl methyl trisulfide (AMT), a constituent of garlic oil, has been synthesized recently. When given p.o. 96 and 48 hr prior to BP, AMT inhibits the occurrence of forestomach tumors in mice. 3. Green coffee beans. Two diterpene esters, kahweol palmitate and cafestol palmitate, which are potent inducers of GSH S-transferase activity have been isolated from coffee beans. When administered p.o. prior to DMBA the two diterpene esters inhibit mammary tumor formation. 4. Cruciferous vegetables. Several glucosinolates occur in cruciferous vegetables. Efficient procedures for the isolation of these compounds have been developed recently. The inhibitory effects of three of these i.e. glucobrassicin, glucotropaeolin, and glucosinalbin were studied in several animal models. Glucobrassicin caused substantial inhibition of BP-induced neoplasia of the lung and forestomach of the mouse and DMBA-induced neoplasia of the breast in rats. Glucosinalbin and glucotropaeolin are less active in these systems. In addition to protective effects, indoles derived from the hydrolysis of glucobrassicin have potential harmful properties. The implications of multiple properties and factors which may determine their consequence will be discussed.

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↗
PubMed1983

Effect of steroid hormone treatment on aryl hydrocarbon hydroxylase activity in the Syrian hamster kidney.

Aryl hydrocarbon hydroxylase (AHH) activity was determined in castrate and intact male Syrian hamster kidney and liver microsomes following in vivo treatment with either diethylstilbestrol (DES) or 17 beta-estradiol as well as other steroid hormones. After 1 month of estrogen treatment, there was a 5-fold decline in AHH activity in castrated hamster kidneys compared with untreated castrate levels. The amount of AHH activity in the kidney was depressed more than 75% of untreated castrate levels even after the estrogen had been withdrawn for 6 days. Consistent with a nearly 2.5-fold higher renal AHH activity observed in intact male hamsters compared to castrates was the finding of a 1.7-fold elevation in the activity of this enzyme after treatment of castrated animals with androgen[5 alpha-dihydrotestosterone (5 alpha-DHT)] for 1 month. Moreover, following withdrawal of estrogen from intact hamsters, the increase in AHH activity in the kidney essentially paralleled the rise in serum testosterone levels. In castrated animals, the depression of AHH activity by estrogen was partially reversed by concomitant 5 alpha-DHT treatment. However, no appreciable changes were seen in liver AHH activity with androgen treatment in the presence or absence of estrogen. Similarly, the level of AHH activity, which was nearly 7- and 14-fold higher than intact and castrate kidney levels, respectively, was not altered by estrogen treatment. Neither progesterone nor cortisone had any effect on the levels of AHH activity in either the kidney or liver. Therefore, AHH activity in the male hamster kidney, but not the liver, is responsive to both estrogens and androgenic hormone.

Animals↗
PubMed1983

Relative carcinogenic activity of various synthetic and natural estrogens in the Syrian hamster kidney.

Both synthetic and natural estrogens have been studied for their ability to induce renal carcinomas in castrated male hamsters after 9.0 months of treatment. Tumor foci were detected in frozen serial sections stained histochemically for estrase activity. Both diethylstilbestrol (DES) and 17 beta-estradiol had equal ability (100%) to induce renal tumors [approximately 20.5 +/- 3 (S.E.) tumor foci] in these animals. Hexestrol induced the same incidence and number of renal carcinoma foci as DES or 17 beta-estradiol. However, alpha -dienestrol and DES 3,4-oxide showed an 86 to 88% incidence of renal tumors in hamsters (approximately 10.8 +/- 3). When equilin and d-equilenin, components of therapeutic conjugated estrogens, were tested, only equilin had a 76% incidence of renal tumor foci (5.5 +/- 0.9). The ability of these stilbene and steroidal estrogens to compete for renal tumor estrogen receptor generally correlated well with their ability to cause renal tumorigenesis in the hamster with one notable exception. Although ethinyl estradiol competed as well as did DES or 17 beta-estradiol for estrogen receptor, had similar ability to induce renal progesterone receptor, and led to similar high serum prolactin levels as either DES or 17 beta-estradiol, it had only weak carcinogenic activity (21%) in the hamster kidney (0.6 +/- 0.5 foci). These data represent the first detailed analysis of the relative carcinogenic activity of different estrogens within a given tumor-inducing system, and based on the carcinogenicity data of hexestrol and alpha-dienestrol presented herein, they suggest that epoxidation of the olefinic double bond and the p-quinone metabolite of DES probably are not involved significantly in its carcinogenic activity. Moreover, the poor carcinogenic activity of ethinyl estradiol in this system, despite strong estrogenicity, suggests that estronic activity alone may not be sufficient to effect renal tumorigenesis in the hamster.

Adenocarcinoma↗
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↗
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

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↗