• Toxicological Research
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• v.2 no.1
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• pp.1-7
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• 1986

Procarcinogen induced DNA single-strand breaks and unschduled DNA synthesis were measured in primary rat hepatocytes culture. For DNA single-strand breaks assay, rat liver DNA was prelabeled by injection 3H-thymidine during the peak of DNA synthesis following partial hepatectomy. Hepatocytes were isolated from the rat 2 weeks after surgery by a collagenase perfusion techinique and maintained as monolayers in serum free medium on collagen-coated culture dishes. DNA sigle-strand breaks were measured by the alkaline elution techinique.

• Archives of Pharmacal Research
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• v.22 no.5
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• pp.474-478
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• 1999

Modulation of unscheduled DNA synthesis by dehydroepiandrosterone (DHEA) after exposure to various chemical carcinogens was investigated in the primary rat hepatocytes. Unscheduled DNA synthesis was induced by treatment of such direct acting carcinogens as methly methanesulfonate (MMS) and ethyl methanesulfonate (EMS) or procarcinogens including benzo(a)pyrene (BaP) and 7, 12-dimethylbenz(a)anthracene (DMBA). Unscheduled DNA synthesis was determined by measuring [methyl-3H]thymidine radioactivity incorporated into nuclear DNA of hepatocytes treated with carcinogens in the presence or absence of DHEA. Hydroxyurea $(5{\times}10^{-3} M)$was added to growth medium to selectively suppress normal replication. DHEA at concentrations ranging from $(1{\times}10^{-6} M)$ to$(5{\times}10^{-4} M)$ did not significantly inhibit unscheduled DNA synthesis induced by either MMS $(1{\times}10^{-4} M)$ or EMS $(1{\times}10^{-2} M)$. In contrast, DHEA-significantly inhibited unscheduled DNA synthesis induced by BaP $(6.5{\times}10^{-5} M)$ and DMBA.$(2{\times}10^{-5} M)$. DHEA-induced hepatotoxicity in rats was examined using lactate dehydrogenase (LDH) release as an indicator of cytotoxicity. DHEA exhibit no significant increase in LDH release compared with the control at 18 h. These data suggest that nontoxic concentration of DHEA does not affect the DNA excision repair process, but it probably influence the enzymatic system responsible for the metabolic activation of procarcinogens and thereby decreases the amount of the effective DNA adducts formed by the ultimate reactive carcinogenic species.

• Toxicological Research
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• v.4 no.2
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• pp.131-142
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• 1988

The post-mitochondrial liver fractions (S-9) were prepared from rats and hamsters which have been treated with Aroclor 1254 (PCB) and the capacities of these S-9 fractions to generate mutagenic metabolites from several well known procarcinogens have been compared. Benzo(a)pyrene (B(a)P), 3-methylcholanthrene (3-MC), Aflatoxin B1(AFB1), 2-acetylamino-fluorene(AAF), and 2-aminofluorene (AF) were employed as promutagens in the Salmonella reverse mutation tests. Results showed that the rat and hamster S-9 fractions had differential abilities to produce mutagenic metabolites from a given promutagen.

• Proceedings of the Korean Society of Toxicology Conference
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• 2003.10b
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• pp.169-169
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• 2003

CYP1 enzymes, CYP1A1, CYP1A2 and CYP1B1, are known to bioactivate procarcinogens particularly polyaromatic compounds. Flavonoids are a class of natural compounds that are present in edible plants. Structurally, these compounds are polyphenols with two aromatic rings (A, B) and a heterocycyclic ring (C).(omitted)

• Journal of the Korean Society of Food Science and Nutrition
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• v.27 no.5
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• pp.968-972
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• 1998

Allium tuberosum Rotter(Liliaceae) is a perennial herb of which leaves are used for food. Leek has been reported to have pharmacological effects including alleviations of abdominal pain, diarrhea, hematemesis, snakebite, and asthma. To investigate the effect of dietary leek supplementation on the drug-metaboizing enzymes, quinone reductase(QR) and arylhydrocarbon hydroxylase(AHH) activities in the liver, stomach, small intestine and lung, and on the plasma testosterone and dihydrosterone hormone levels, mice were fed 2% and 5% leek diets for 8 weeks. Quinone reductase, an anticarcinogenic enzyme, was significantly induced in stomach, small intestine, and lung but slightly lowered in hepatic tissue in the experimental groups compared to control group. Arylhydrocarbon hydroxylase activity, involved in bioactivation of procarcinogens, was significantly decreased in liver and lung. Leek feeding led to the reduction in the plasma level of dihydrotestosterone which is associated with the incidence of prostate cancer. These findings support the potential chemopreventive activity of leek supplementation.

• Proceedings of the PSK Conference
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• 2003.10b
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• pp.112.2-112.2
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• 2003

CYP1 enzymes, CYP1A1, CYP1A2 and CYP1B1, are known to bioactivate procarcinogens particularly polyaromatic compounds. Flavonoids are a class of natural compounds that are present in edible plants. Structurally, these compounds are polyphenols with two aromatic rings (A, B) and a heterocycyclic ring (C). We observed the differential inhibition of 5,7-dihydroxyflavones which are different in numbers of B-ring-OH, to the activity of ethoxyresorufin O-deethylase (EROD) in human hepatic microsomes with the IC50 values, ie, 0.57 mM, 1.28 mM, and 3.62 mM, chrysin, apigenin, and Luteolin, respectively. (omitted)

• Archives of Pharmacal Research
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• v.23 no.4
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• pp.267-282
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• 2000

Cytochrome P45O (CYP) 2E1 catalyzes the metabolism of a wide variety of therapeutic agents, procarcinogens, and low molecular weight solvents. CYP2E1-catalyzed metabolism may cause toxicity or DNA damage through the production of toxic metabolites, oxygen radicals, and lipid peroxidation. CYP2E1 also plays a role in the metabolism of endogenous compounds including fatty acids and ketone bodies. The regulation of CYP2E1 expression is complex, and involves transcriptional, post-transcriptional, translational, and post-translational mechanisms. CYP2E1 is transcriptionally activated in the first few hours after birth. Xenobiotic inducers elevate CYP2E1 protein levels through both increased translational efficiency and stabilization of the protein from degradation, which appears to occur primarily through ubiquitination and proteasomal degradation. CYP2E1 mRNA and protein levels are altered in response to pathophysiologic conditions by hormones including insulin, glucagon, growth hormone, and leptin, and growth factors including epidermal growth factor and hepatocyte growth factor, providing evidence that CYP2E1 expression is under tight homeostatic control.

• Korean Journal of Food Science and Technology
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• v.31 no.2
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• pp.535-539
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• 1999

Soybean has drawn much attention mainly due to its chemopreventive action as well as antiestrogenic effect. Although suppression of breast and prostate cancers were believed to be exerted via antiestrogenic or antiandrogenic activity of genistein, its mechanism of prevention against other cancers has not been clearly demonstrated. We proposed that prevention by soybean from other cancers than sex hormone -related cancers was achieved via modulation of drug-metabolizing enzymes. Addition of acid hydrolysate of 80% methanol extract of soyflour to diet caused a significant induction of quinone reductase, an anticarcinogenic marker enzyme and one of drug-metabolizing enzymes, in mouse lung while it suppressed arylhydrocarbon hydroxylase, involved in bioactivation of procarcinogens, in kidney and small intestine. It is likely that active components exist in a conjugated form and released by acid hydrolysis to be able to affect drug-metabolizing enzyme and exert chemopreventive activity. Benzo(a)pyrene-induced tumor development in mouse lung was greatly reduced by soybean extract supplementation, which is consistent with the extract's capability to modulate favorably arylhydrocarbon hydroxylase and quinone reductase towards chemoprevention.

• Archives of Pharmacal Research
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• v.27 no.2
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• pp.199-205
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• 2004

Cytochrome P450 (P450) 1 enzymes such as P450 1A1, 1A2, and 181 are known to be involved in the oxidative metabolism of various procarcinogens and are regarded as important target enzymes for cancer chemoprevention. Previously, several hydroxystilbene compounds were reported to inhibit P450 1 enzymes and were rated as candidate chemopreventive agents. In this study, we investigated the inhibitory effect of 2-[2-(3,5-dimethoxyphenyl)vinyl]-thiophene (DMPVT), produced from the chemical modification of oxyresveratrol, on the activities of P450 1 enzymes. The inhibitory potential by DMPVT on the P450 1 enzyme activity was evaluated with the Escherichia coli membranes of the recombinant human cytochrome P450 1A1, 1A2, or 1B1 coexpressed with human NADPH-P450 reductase. DMPVT significantly inhibited ethoxyresorufin O-deethylation (EROD) activities with $IC_{50}$ values of 61, 11, and 2 nM for 1A1, 1A2, and 1B1, respectively. The EROO activity in OMBA-treated rat lung microsomes was also significantly inhibited by OMPVT in a dose-dependent manner. The modes of inhibition by DMPVT were non-competitive for all three P450 enzymes. The inhibition of P450 1B1-mediated EROD activity by OMPVT did not show the irreversible mechanism-based effect. The loss of EROD activity in P450 1B1 with OMPVT incubation was not blocked by treatment with the trapping agents such as glutathione, N-acetylcysteine, or dithiothreitol. Taken together, the results suggested DMPVT to be a strong noncompetitive inhibitor of human P450 1 enzymes that should be considered as a good candidate for a cancer chemopreventive agent in humans.