Benefits of aged garlic extract in modulating toxicity biomarkers against p-dimethylaminoazobenzene and phenobarbital induced liver damage in Rattus norvegicus.

Garlic (Allium sativum L.), a popular spice, has been used for decades in treating several medical conditions. Although Allicin, an active ingredient of garlic has been extensively studied on carcinogen-induced hepatotoxicity and oxidative stress in rats (Rattus norvegicus), no systematic study on the beneficial effects of generic aged garlic and specific aged garlic extract-Kyolic has been done. The present study involves rats fed chronically with two liver carcinogens, p-dimethylaminoazobenzene and phenobarbital, to produce hepatotoxicity. The aged garlic extract was characterized by UV-spectra, FTIR, HPLC and GC-MS. Biochemical and pathophysiological tests were performed by keeping suitable controls at four fixation intervals, namely, 30, 60, 90, and 120 days, utilizing several widely accepted toxicity biomarkers. Compared to the controls, remarkable elevation in the activities of lactate dehydrogenase, gamma glutamyl transferase and decline in catalase and glucose-6-phosphate dehydrogenase were observed in the carcinogen fed rats. Daily administration of aged garlic extract, could favorably modulate the elevated levels of various toxicity biomarkers including serum triglyceride, creatinine, urea, bilirubin, blood urea nitrogen except total cholesterol. It also altered the levels of blood glucose, HDL-cholesterol, albumin, AST, ALT, and hemoglobin contents in carcinogen intoxicated rats, indicating its protective potential against hepatotoxicity and oxidative stress in the experimental rats. Down-regulation of Bcl-2 and p53 proteins caused cell cycle arrest and apoptosis in garlic fed group. Kyolic exhibited additional benefits by arresting cell viability of cancer cells. This study would thus validate the use of aged garlic extract in the treatment of diseases causing liver toxicity including hepatocarcinoma.

Role of ErbB2 mediated AKT and MAPK pathway in gall bladder cell proliferation induced by argemone oil and butter yellow. Argemone oil and butter yellow induced gall bladder cell proliferation.

The effect of noncytotoxic doses of argemone oil (AO) and butter yellow (BY), the common adulterants in edible oil, on free radical generation and signaling pathway for cell proliferation in primary cells of gall bladder (GB) was undertaken. AO and BY showed no cytotoxicity at 0.1 µl/ml and 0.1 µg/ml concentration, respectively. AO caused significant increase in ROS after 30 min and RNS after 24 h in GB cells while no change was observed following BY treatment. Enhanced level of COX-2 was observed following AO (0.1 µl/ml) and BY (0.1 µg/ml) treatment to cells for 24 h. AO treatment caused phosphorylation of ErbB2, AKT, ERK, and JNK along with increased thymidine uptake indicating cell proliferation ability in GB cells. BY treatment also showed significant expression of these proteins with the exception of phosphorylated JNK. These results suggest that AO and BY have cell proliferative potential in GB cells following up-regulation of COX-2 and ErbB2; however, their downstream signaling molecules and free radical generation have differential response, indicating that the mechanism of proliferation is different for both compounds and may have relevance in gall bladder cancer.

[Parasitic factor and cancer].

There is opinion in the literature as to that liver trematode infections, such as opisthorchiasis, clonorchiasis, fascioliasis, and metorchiasis, can induce cancer of the liver pancreas, intestine - this all is clinically observed. The authors were the first in world practice to show the development of a hepatic blastomatous process in animals (albino rats, cats) with opisthorchiasis in 13%; cancer developed in 28 and 56% with the use of a hepatotropic carcinogen and combined (opisthorchiasis + a carcinogen) exposure, respectively. Throughout his life, a human being can easily catch these trematodes that have carcinogenic activity and these diseases concurrent with household and food carcinogens can give rise to tumors in the liver pancreas and intestine. Timely diagnosis and specific anthelmintic therapy are necessary to prevent parasitic cancer.

Effect of antioxidant vitamins A, C, E and their analogues on azo-dye binding protein in liver of rats treated with p-dimethylaminoazobenzene.

p-Dimethylaminoazobenzene (DAB) is an azo-dye and known to cause liver tumour in rats. Azo-dye binding protein is a specific cytosolic protein involved in the translocation of azo-dye carcinogen metabolites from liver cytoplasm into the nucleus. Administration of vitamin A (40,000 and 50,000 IU), L-ascorbic acid (500 and 1000 mg) and vitamin E succinate (200-500 mg) reduced the amount of azo-dye binding protein in liver of rats treated with DAB. Supplementation of high doses of vitamin A acetate, vitamin A palmitate, sodium ascorbate, ascorbyl palmitate and vitamin E acetate had no effect on the quantity of azo-dye binding protein in liver. When the vitamin mixture was given, the level of azo-dye binding protein decreased in the liver at all the studied doses, which may be due to their synergistic effect.

Efficacy of a plant extract (Chelidonium majus L.) in combating induced hepatocarcinogenesis in mice.

Ethanolic whole plant extract of Chelidonium majus, extensively used in traditional systems of medicine against various liver ailments, has been tested for its possible anti-tumor, hepato-protective and anti-genotoxic effects in p-dimethylaminoazobenzene (p-DAB) induced hepatocarcinogenesis in mice through multiple assays: cytogenetical, biochemical, histological and electron microscopical. Different sets of mice, 5 (for 7, 15 and 30 days' treatment) or 10 (for 60, 90 and 120 days) each, were chronically fed a diet suitably mixed with p-DAB and phenobarbital to develop liver tumors. One sub-group of carcinogen fed mice was also fed C. majus extract; 0.1 ml daily (drug-treated) while the other equal amount of dilute ethyl alcohol ("vehicle" of plant extract) (positive control). A separate group of mice was maintained with normal diet without any carcinogen treatment (negative control). Data of several cytogenetical endpoints and biochemical assay of some toxicity marker enzymes at all fixation intervals and histology of liver sections through ordinary, scanning and transmission electron microscopy at 60 and 120 days and that of spleen and kidney at 90 days were critically analyzed in the treated lots vis-a-vis controls. The results suggest anti-tumor, anti-genotoxic and hepato-protective effects of the plant extract, showing potentials for use in cancer therapy.

Dietary supplementation of vitamin A, C and E prevents p-dimethylaminoazobenzene induced hepatic DNA damage in rats.

The preventive effect of antioxidant vitamins A, C, E and their analogues against DNA damage induced by a hepatocarcinogen p-dimethylaminoazobenzene (DAB) was assessed by comet assay. For genotoxicity (DNA damage) study, male albino rats were divided into 11 groups, consisting of four rats each. Group I served as control. Group II to VII received 1, 10, 100, 200, 300 and 400 mg per kg body wt of DAB respectively; group VIII to XI received 500 mg/kg body wt of DAB. They were sacrificed by cervical decapitation 3, 6, 12 and 24 h after treatment; livers were excised immediately and subjected to comet assay to measure DNA damage. To study the effect of vitamins, experiments were conducted on a group of 275 rats divided into 3 sets of 25 rats each. First set served as control; second set received 0.06% DAB and third set received 0.06% DAB, along with analogues of vitamins A, C and E. Rats fed with 0.06% DAB were provided water ad libitum for a period of 4 months, followed by a normal (basal) diet for further 2 months. Vitamins A (10,000-50,000 IU), C (75-1000 mg) and E (50-500 mg) and their analogues were given (per kg body wt) to the third set of rats by gavage route once in a week for a period of 6 months. The DAB induced DNA damage only at the highest tested dose of 500 mg/kg body wt. Administration of high doses of vitamin A acid, L-ascorbic acid and vit. E succinate individually prevented the DNA damage. However, administration of a mixture of these vitamins at low doses prevented the DAB-induced DNA damage, which may be due to their synergistic effect. The results indicate that there is a significant advantage in mixed vitamins therapy at low dose over the treatment with individual vitamins.

Effect of bromide on the transformation and genotoxicity of octyl-dimethyl-p-aminobenzoic acid during chlorination.

Octyl-dimethyl-p-aminobenzoic acid (ODPABA), one of the most commonly used organic UV filters, can undergo considerable transformation in water when entering into the disinfection process. The impacts of bromide on degradation kinetics, formation and speciation of transformation products, regulated disinfection by-products (DBPs) as well as genotoxicity changes during ODPABA chlorination were investigated in this study. Results indicated that the reaction of ODPABA with chlorine followed pseudo-first-order and second-order kinetics. Adding bromide noticeably enhanced the degradation rate of ODPABA, but reduced the impact of chlorine dose. Four halogenated transformation products (Cl-ODPABA, Br-ODPABA, Cl-Br-ODPABA and Br2-ODPABA) were detected by LC-MS/MS. Mono-halogenated products were stable during 24-h chlorination, while di-halogenated products constantly increased. The total yields of trihalomethanes (THMs) and haloacetic acids (HAAs) were both low, but predominated by bromine substitution at high levels of bromide. In addition, SOS/umu tests showed that genotoxicity was generated after ODPABA chlorination, which was increased at least 1.5 times in the presence of bromine. Whereas, no significant genotoxicity variation was observed following bromide concentration change.

Homeostatic response under carcinogen withdrawal, heme oxygenase 1 expression and cell cycle association.

BACKGROUND: Chronic injury deregulates cellular homeostasis and induces a number of alterations leading to disruption of cellular processes such as cell cycle checkpoints and apoptosis, driving to carcinogenesis. The stress protein heme oxygenase-1 (HO-1) catalyzes heme degradation producing biliverdin, iron and CO. Induction of HO-1 has been suggested to be essential for a controlled cell growth. The aim of this work was to analyze the in vivo homeostatic response (HR) triggered by the withdrawal of a potent carcinogen, p-dimethylaminoazobenzene (DAB), after preneoplastic lesions were observed. We analyzed HO-1 cellular localization and the expression of HO-1, Bcl-2 and cell cycle related proteins under these conditions comparing them to hepatocellular carcinoma (HC). METHODS: The intoxication protocol was designed based on previous studies demonstrating that preneoplastic lesions were evident after 89 days of chemical carcinogen administration. Male CF1 mice (n = 18) were used. HR group received DAB (0.5 % w/w) in the diet for 78 days followed by 11 days of carcinogen deprivation. The HC group received the carcinogen and control animals the standard diet during 89 days. The expression of cell cycle related proteins, of Bcl-2 and of HO-1 were analyzed by western blot. The cellular localization and expression of HO-1 were detected by immnunohistochemistry. RESULTS: Increased expression of cyclin E/CDK2 was observed in HR, thus implicating cyclin E/CDK2 in the liver regenerative process. p21cip1/waf1 and Bcl-2 induction in HC was restituted to basal levels in HR. A similar response profile was found for HO-1 expression levels, showing a lower oxidative status in the carcinogen-deprived liver. The immunohistochemical studies revealed the presence of macrophages surrounding foci of necrosis and nodular lesions in HR indicative of an inflammatory response. Furthermore, regenerative cells displayed changes in type, size and intensity of HO-1 immunostaining. CONCLUSION: These results demonstrate that the regenerative capacity of the liver is still observed in the pre-neoplastic tissue after carcinogen withdrawal suggesting that reversible mechanism/s to compensate necrosis and to restitute homeostasis are involved.

Genotoxicity studies OF p-dimethylaminoazobenzene (DAB).

The potential genotoxicity of the rodent liver carcinogen p-dimethylaminoazobenzene (DAB) was evaluated in compliance with the guidelines for genotoxicity studies of drugs (Notification No. 1604, Nov. 1, 1999, Ministry of Health and Welfare, Japan) and the OECD guidelines for testing chemicals. DAB was clearly positive in both the bacterial reverse mutation test (Ames test) and in vitro chromosomal aberration test in the presence of metabolic activation, whereas it was weakly positive at toxic doses in the rat bone marrow micronucleus test. It has been reported that DAB was clearly positive in in vivo genotoxicity tests, i.e., a mouse alkaline single cell gel electrophoresis (comet) assay and a young rat liver micronucleus test. These results suggest that the test system using the liver is effective for in vivo genotoxicity assessment of chemicals that show mutagenicity in in vitro genotoxicity tests in the presence of metabolic activation.

Malignant transformation of rat liver cells by N-benzoyloxy-3'-methyl-4-methylaminoazobenzene and its related compound.

N-Benzoyloxy-3'-methyl-4-methylaminoazobenzene-(N-benzoyloxy-3'-Me-MAB) was highly toxic to rat liver epithelial cells (Ac2F) and induced many more chromosome aberrations and unscheduled DNA synthesis than did 3'-methyl-4-dimethylaminoazobenzene (3'-Me-DAB). N-Benzoyloxy-3'-Me-MAB and its related compound, N-acetoxy-4-methylaminoazobenzene, efficiently induced malignant transformation of the cells, but 3'-Me-DAB was not so effective. The cells transformed by N-acyloxy-4-methylaminoazobenzene (N-acyloxy-MAB) derivatives showed significant increases in plating efficiency in liquid medium and in the size of aggregates in rotation culture. Such increases were not seen in the 3'-Me-DAB-transformed cells. The results indicate that the N-acyloxy form of the 4-dimethylaminobenzene derivatives seems very likely to be the ultimate metabolite.

4-aminoazobenzene and N,N-dimethyl-4-aminoazobenzene as equipotent hepatic carcinogens in male C57BL/6 X C3H/He F1 mice and characterization of N-(Deoxyguanosin-8-yl)-4-aminoazobenzene as the major persistent hepatic DNA-bound dye in these mice.

In contrast to the well-established requirement for an N-methyl group for efficient hepatic tumor induction by dietary administration of derivatives of 4-aminoazobenzene (AB) to adult rats, we have now observed that AB and its N-methyl and N,N-dimethyl derivatives have high and approximately equal hepatocarcinogenicity when given as a single i.p. dose to male 12-day-old C57BL/6 X C3H/ HeF1 (B6C3F1) mice. The hepatoma multiplicity induced by these dyes was approximately linearly related to the dose from 0.017 to 0.15 mumol/g body weight; at the high dose, an average of 11 hepatomas/mouse was observed at 10 months. Female B6C3F1 mice were resistant to tumor induction under these conditions. AB and its N-methyl derivative also induced the same incidences of hepatomas on administration of a single dose of 0.45 mumol/g body weight to 12-day-old male C3H/He mice (about 15 hepatomas/mouse) or C57BL/6 mice (about 1 hepatoma/mouse). Infant male Fischer rats were much less susceptible; less than 25% of the rats given 4 i.p. injections (0.3 to 0.4 mumol/g of body weight/injection) of N-methyl-4-amino-azobenzene and less than or equal to 5% of those given these doses of N,N-dimethyl-4-aminoazobenzene or AB before 22 days of age developed hepatic carcinomas by 24 months. Reverse-phase high-performance liquid chromatography of enzymatically hydrolyzed hepatic DNA from 12-day-old male B6C3F1 mice or Fischer rats given an i.p. dose (0.08 or 0.3 mumol/g of body weight) of [prime-ring-3H]AB showed a single major adduct which was chromatographically identical to N-( deoxyguanosin -8-yl)-4-aminoazobenzene synthesized by reaction at pH 7 of N-acetoxy-4-aminoazobenzene (formed in situ from N-hydroxy-4-aminoazobenzene and acetic anhydride) with deoxyguanosine. Mouse and rat liver DNA contained 20 and 0.5 pmol, respectively, of this adduct per mg 24 hr after administration of 0.3 mumol of [prime-ring-3H]AB/g of body weight. At 24 hr after administration of N,N-[prime-ring-3H]dimethyl-4-aminoazobenzene to male B6C3F1 mice, N-( deoxyguanosin -8-yl)-4-aminoazobenzene, N-( deoxyguanosin -8-yl)-N-methyl-4-aminoazobenzene, and 3-( deoxyguanosin -N2-yl)-N-methyl-4-aminoazobenzene were present in a ratio of approximately 4:2:1, respectively. Unlike the N-( deoxyguanosin -8-yl)-N-methyl-4-aminoazobenzene adducts, the N-( deoxyguanosin -8-yl)-4-aminoazobenzene adducts were relatively stable in the DNA; the level of the latter adducts decreased about 60% between 24 hr and 21 days.(ABSTRACT TRUNCATED AT 400 WORDS)

Cytotoxic and genotoxic effects of the azo-dye p-dimethylaminoazobenzene in mice: a time-course study.

The cytotoxic and genotoxic effects of chronic feeding of the azo-dye p-dimethylaminoazobenzene (p-DAB) during 7, 15, 30, 60, 90 and 120 days have been assessed in mice. The endpoints used for genotoxic analysis were chromosome aberrations (CA), micronuclei (MN) and mitotic index (MI) in bone-marrow cells, and sperm-head abnormality (SHA) in male gonads. The activities of marker enzymes for toxicity, such as glutamate oxalo-acetate transaminase (GOT), glutamate pyruvate transaminase (GPT), acid phosphatase (ACP) and alkaline phosphatase (ALKP) were also assayed periodically, as was lipid peroxidation (LPO). Chronic feeding of p-DAB produced increased numbers of chromosome aberrations, nuclear anomalies and sperm-head abnormalities, as compared with normal untreated controls, generally in a time-dependent manner until 60 days, after which the anomalies persisted, but rather erratically. However, although there was some noticeable modulation in enzyme activities in the corresponding p-DAB-fed mice as well, these were not strictly time-dependent.

Evaluation of liver and peripheral blood micronucleus assays with 9 chemicals using young rats. A study by the Collaborative Study Group for the Micronucleus Test (CSGMT)/Japanese Environmental Mutagen Society (JEMS)-Mammalian Mutagenicity Study Group (MMS).

We conducted simultaneous liver and peripheral blood micronucleus assays in young rats with seven rodent hepatocarcinogens-4,4'-methylenedianiline (MDA), quinoline, o-toluidine, 4-chloro-o-phenylenediamine (CPDA), dimethylnitrosamine (DMN), p-dimethylaminoazobenzene (DAB), and di(2-ethylhexyl)phthalate (DEHP)-and two mutagenic chemicals-kojic acid and methylmethanesulfonate (MMS). Quinoline, DMN, and DAB were positive in the liver assay, while o-toluidine, kojic acid, DAB, and MMS were positive in the peripheral blood assay. o-Toluidine, kojic acid, and DAB are reportedly negative in mouse bone marrow micronucleus assays, indicating a species difference. Our results revealed a correlation between micronucleus induction in hepatocytes and hepatocarcinogenicity. This technique can be useful for the detection of micronucleus-inducing chemicals that require metabolic activation, and it enables simultaneous comparison of the micronucleus-inducing potential of chemicals in the liver and peripheral blood in the same individual.

Evaluation of the repeated-dose liver micronucleus assay with p-dimethylaminoazobenzene.

The micronucleus induction by p-dimethylaminoazobenzene (DAB), a genotoxic rat liver carcinogen, was assessed in the liver and bone marrow of young adult rats after the repeated administration of DAB for 14 (Lab. 1) and 28 (Lab. 2) days. Three dose levels, 25, 50 and 100mg/kg/day, were used for the investigations in both labs. The frequency of micronucleated hepatocytes was significantly increased in a dose-dependent manner after the repeated administration of DAB at 50mg/kg/day or more for 14 and 28 days. Similarly, the frequency of micronucleated immature erythrocytes in the bone marrow was increased after the repeated administration of DAB at 100mg/kg/day for 14 and 28 days. These results indicate that the repeated-dose liver micronucleus assay allowed for the detection of micronucleus induction by DAB, and that the lowest detectable dose for micronucleus induction in the liver was lower than in the bone marrow. Thus, the repeated-dose liver micronucleus assay using young adult rats is considered suitable for the detection of micronucleus induction by liver carcinogens, such as DAB.

On the promoting action of tamoxifen in a model of hepatocarcinogenesis induced by p-dimethylaminoazobenzene in CF1 mice.

BACKGROUND AND AIMS: Tamoxifen (TMX) has proven to be an effective palliative treatment for advanced breast cancer with low reported incidence of side effects. TMX has been demonstrated to be an initiator and/or a promoter in the rat model of hepatocarcinogenesis. To document the long-term effect of TMX in mice treated with p-dimethylaminoazobenzene (DAB), we have investigated the time response action of these drugs on different biochemical parameters. METHODS: A group of animals was placed on dietary DAB (0.5%, w/w) during a period of 28 weeks. Control animals received a standard laboratory diet. Two other groups of non-treated and DAB-treated animals received TMX citrate (0.025%, w/w) in the diet since day 20. RESULTS: The activities of the enzymes involved in heme synthesis and degradation as evaluated in the DAB group was not further affected by TMX. DAB and/or TMX treatment significantly increased the content of total cytochrome P450 and also the activity of glutathione S-transferase indicating liver damage. In all treated groups oxidative stress and an adaptive response of the natural defense system (catalase and superoxide dismutase) were demonstrated. Histological and morphological studies revealed liver cell hyperplasia in DAB treated group; however, only in the DAB+TMX group solid, trabecular and acinar hepatocellular carcinoma was confirmed at the end of the experimental trial. CONCLUSION: We have demonstrated that TMX produced changes in hepatic enzyme activities which may be relevant for the metabolism and disposition of this and/or other drugs. Because liver tumors could be initiated and promoted by several agents which need to be activated, the possible hazard of TMX should be considered. This study reports that long-term treatment with TMX enhances hepatocarcinogenesis induced by DAB. The widespread use of TMX as an anticancer agent adds to the significance of this study.

6-p-Dimethylaminophenylazobenzothiazole: a potent hepatocarcinogen in the rat.

6-p-Dimethylaminophenylazobenzothiazole (6BT) administered at a dose of 10 mg/kg by gavage to Sprague-Dawley and Wistar-derived rats for 2 months produced marked cellular changes in the liver, including proliferation of oval cells and the formation of regenerative/hyperplastic nodules. Cellular change continued after stopping dosing at 2 months such that liver tumours were first observed after only 4 months into the study, and animals examined between 4 months and termination at 6 months showed a 75% and 85% incidence of hepatocellular carcinoma for the Sprague-Dawley and Wistar strains, respectively. This study establishes 6BT as a potent hepatocarcinogen in the rat when administered by gavage, and confirms and extends an initial brief report by Brown and Sanchorawala in 1968 of its carcinogenicity following dietary administration.

Dose responses of five hepatocarcinogens for the initiation of rat hepatocarcinogenesis.

Using the Solt and Farber model (Nature, 263 (1976) 701), dose-response relationships between initiating agents and the induction of hyperplastic nodules in rat liver were investigated. Male Fischer 344 rats were initiated by a single application of 1 of 5 carcinogens at 3 doses: 200.0, 50.0 and 12.5 mg/kg of diethylnitrosamine (DEN); 1.00, 0.25 and 0.062 mg/kg of aflatoxin B1 (Af-B1); 60.0, 15.0 and 3.75 mg/kg of N-2-fluorenylacetamide (2-FAA); 600.0, 150.0 and 37.5 mg/kg of 3'-methyl-4-dimethylaminobenzene (3'-me-DAB); 40.0, 10.0 and 2.5 mg/kg of dimethylnitrosamine (DMN) and their vehicles. Two weeks after initiation, animals were placed on a 0.02% 2-FAA diet for 2 weeks. Partial hepatectomy was performed at the end of the third week of the experiment. All rats were killed 4 weeks after the initiation, and the hyperplastic nodules of the liver were counted and their areas measured. Dose responses were observed in both numbers and areas of hyperplastic nodules per unit area of sections with all of the 5 carcinogens examined.

Lack of response of the rat liver "class 3" cytosolic aldehyde dehydrogenase to toxic chemicals, glutathione depletion, and other forms of stress.

One of the rat liver "Class 3" cytosolic aldehyde dehydrogenases (EC 1.2.1.3), ALDH3c, is known to be markedly induced by polycyclic aromatic hydrocarbons and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; dioxin). In the present study we examined whether hepatic ALDH3c induction is a general response to toxicity. Treatment of Wistar rats for 4 days with known toxic doses of hepatotoxic agents--carbon tetrachloride, dimethylnitrosamine, diethylnitrosamine, aflatoxin B1, and D-ethionine--did not induce ALDH3c enzyme activity. Whereas dimethylaminoazobenzene at 100 mg/kg/day for 4 days did not increase ALDH3c, a 10-fold lower dose of dimethylaminoazobenzene for 4 days produced a 20-fold increase in ALDH3c activity. Treatment with phorone, diethylmaleate or L-buthionine-S,R-sulfoximine--which deplete reduced glutathione (GSH) by different mechanisms--did not affect ALDH3c activity. One dose of benzo[a]pyrene for 24 hr increased ALDH3c activity by 25-fold. Treatment with both the GSH-depleting chemicals and benzo[a]pyrene inhibited ALDH3c induction by 45% to 75%, suggesting a role for GSH during ALDH3c induction. After ALDH3c activity had already been induced by benzo[a]pyrene, however, the GSH-depleting chemicals did not affect ALDH3c activity. No changes in ALDH3c activity were seen 24 or 48 hr after partial hepatectomy, on the fifth day following surgical cholestasis, or after guanethidine-induced sympathectomy. These data indicate that hepatic ALDH3c inducibility in the rat is not a general or direct response to chemical toxicity, or to conditions of GSH depletion or other forms of stress.

beta-Carotene partially prevents the damage induced by 1,4-dimethylaminoazobenzene in mice.

Hepatocarcinogenesis (HC) induced by various carcinogens such as 1,4-dimethylaminoazobenzene (DAB) is a multistep and complex process. The anticancer efficacy of beta-carotene (beta C) was evaluated by estimating some biochemical parameters during the initiation stage of HC. beta C dietary supplementation partially prevented the rise in delta-aminolevulinate synthetase activity. P 450 levels were dramatically enhanced in all groups studied. beta C administration did not overcome catalase inactivation due to DAB treatment; however, superoxide dismutase activity levels showed to be less decreased in the DAB + beta C animals in comparison to the DAB group. The great enhancement provoked by DAB of glutathione S-transferase, a proposed marker of HC, was partially reversed by beta C. In conclusion, heme pathway regulation, drug metabolism, and natural oxidative defence systems, strikingly modified in DAB fed animals, were partially controlled by provitamin A. The potential use of beta C in preventing carcinogenesis is suggested.

65Zn uptake by liver of rats fed 3'-methyl-dimethylaminoazobenzene.

The uptake of 65Zn, determined by gamma-counting and also by autoradiography, significantly increased with the increasing level of metallothionein in liver 4 weeks after the start of feeding a diet containing 3'-methyl-dimethylaminoazobenzene (3'-Me-DAB), at which time the serum gamma-glutamyl transpeptidase activity was not yet significantly elevated. At this time, furthermore, hepatic uptake of 67Ga-citrate did not increase and that of 99mTc-Sn-colloid decreased in 3'-Me-DAB-fed rats. These results suggest that a short-life gamma-emitting isotope such as 69mZn may be useful for the detection at the early stage of hepatic carcinogenesis.