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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Steroid hormones, such as estrogens, appear to be associated with ovarian carcinogenesis, but the precise biological mechanisms are unclear. Polymorphisms in genes that regulate the concentration of estrogens and their metabolites may contribute directly to the individual variation in ovarian cancer risk through a mechanism involving oxidative stress or indirectly by influencing ovarian cancer susceptibility associated with ovulation and reproduction. We conducted a population-based, case-control study of primary ovarian cancer between 1993 and 1999 in Hawaii to test several genetic and related hypotheses. A personal interview and blood specimen were obtained in the subjects' homes. In a sample of 129 epithelial ovarian cancer cases and 144 controls, we compared the frequencies of several polymorphisms in genes that regulate steroid hormone metabolism and catecholestrogen formation. Multivariate unconditional logistic regression was used to model the association of each genetic polymorphism separately after adjusting for age, ethnicity, and other covariates. The high-activity Val432 allele of the CYP1B1 gene, which may be linked to oxidative stress through elevated 4-hydroxylated catecholestrogen formation, was associated with an increased risk of ovarian cancer. The Val/Leu genotype for CYP1B1 was associated with an odds ratio of 1.8 (95% confidence interval, 1.0-3.3) and the Val/Val genotype with an odds ratio of 3.8 (95% confidence interval, 1.2-11.4) compared with the Leu/Leu genotype (P = 0.005). Tobacco smokers with at least one CYP1A1 (MspI) m2 allele, one CYP1B1 Val allele, one COMT Met allele, or two CYP1A2 A alleles were at significantly increased risk of ovarian cancer compared to never-smokers with CYP1A1 (MspI) ml/ml, CYP1B1 Leu/Leu, COMT Val/Val, or CYP1A2 A/A genotypes, respectively. We found a positive statistical interaction (P = 0.03) between tobacco smoking and the CYP1A1 (MspI) polymorphism on the risk of ovarian cancer. None of the other gene-environment (pregnancy, oral contraceptive pill use) or gene-gene interactions were statistically significant. Although not significant, there was a suggestion that the effect of the CYP1B1 Val allele was reduced substantially in the presence of the high-activity COMT Met allele. These findings suggest that the CYP1B1-Val allele and perhaps other genetic polymorphisms in combination with environmental or hormonal exposures are susceptibility factors for ovarian cancer.
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PMID:Case-control study of ovarian cancer and polymorphisms in genes involved in catecholestrogen formation and metabolism. 1130 89

Metabolism of toxins and carcinogens is carried out by large groups of xenobiotic-metabolizing enzymes. These enzymes are generally considered to be required for elimination of xenobiotics such as drugs, dietary chemicals and environmental pollutants, and to be required for chemical toxicity and carcinogenicity. An important role for these enzymes in metabolism of endogenous chemicals has not been established. Mouse lines in which the genes encoding several xenobiotic-metabolizing enzymes were knocked out were produced and are being used to determine the role of metabolism in carcinogenesis, and acute and chronic toxicities in vivo. Mouse lines lacking the P450s CYP1A1, CYP1A2, CYP1B1 and CYP2E1, microsomal epoxide hydrolase (mEH), NADPH:quinone oxidoreductase and the glutathione S-transferase P1 have no deleterious phenotypes, indicating that these enzymes are not required for mammalian development and physiological homeostasis. However, when challenged with toxins and carcinogens, they respond differently from their wild-type (WT) counterparts. For example, mice lacking CYP1A2 and CYP2E1 are totally resistant to acetaminophen-induced hepatotoxicity. Mice lacking CYP1B1 or mEH are less responsive to tumorigenesis by 7,12-dimethybenz[a]anthracene. However, CYP1A2-null mice do not significantly differ from WT mice in their response to the hepatocarcinogen 4-aminobiphenyl. These and other studies indicate that the xenobiotic-metabolism null mice are of great value in the study of the mechanisms of chemical injury.
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PMID:The use of gene knockout mice to unravel the mechanisms of toxicity and chemical carcinogenesis. 1132 78

Syrian hamsters treated with estrogen and androgen for 8 months develop leiomyosarcomas in the vas deferens. Metabolism of estrogen by cytochrome P450s (CYPs) produces catechols and reactive oxygen species, and may contribute to tumor formation. To examine this issue, male hamsters were treated with 17 beta-estradiol (E2), testosterone propionate (TP) or both hormones. Reproductive tract tissues from control and treated animals were immunostained with antibodies specific for four CYP enzymes (1A1, 1A2, 1B1 and 3A1/2). Immunoreactive CYP1A1 was not found in the reproductive tract of control or treated animals. In untreated hamsters, CYP1A2 was detected only in principal cells of the caput epididymis. TP alone had no effect, but treatment with E2 induced expression of CYP1A2 in columnar epithelial cells throughout the epididymis and lining of the vas deferens. Treatment with E2 + TP blocked the induction of CYP1A2 seen in surface epithelial cells treated with E2 alone, but not the constitutive expression of this enzyme. Instead, simultaneous exposure to both hormones induced CYP1A2 in basal cells of the epididymis and vas deferens. CYP3A1/2 was not detected in the reproductive tract of control or TP-treated males, but immunostaining was induced in the inner layer of vas deferens smooth muscle by E2, and in all smooth muscle layers by dual hormone treatment. In controls, CYP1B1 was present in smooth muscle lining the epididymis and surrounding the vas deferens and dual hormone treatment increased staining intensity for CYP1B1 in these cells. Immunoreactive CYP1A2 was not detectable in leiomyosarcomas but the enzyme was present in both columnar and basal cells of the vas deferens epithelium adjacent to the tumors. In contrast, tumor cells showed heterogeneous expression of both CYP1B1 and CYP3A1/2. The relationships between hormone treatment, differential CYP expression and tumor formation strengthen our hypothesis that metabolism of estrogen is an important element in this model of hormonal carcinogenesis.
Carcinogenesis 2001 May
PMID:Steroid hormones modulate expression of cytochrome P450 enzymes in male hamster reproductive tract and leiomyosarcomas. 1132 96

The importance of environmental and dietary arylamines, and heterocyclic amines in the etiology of human cancer is of growing interest. These pre-carcinogens are known to undergo bioactivation by cytochrome P450 (CYP)-directed oxidation, which then become substrates for the UDP-glucuronosyltransferases (UGTs). Thus, glucuronidation may contribute to the elimination of CYP-mediated reactive intermediate metabolites, preventing a toxic event. In this study, human UGTs were analyzed for their ability to modulate the mutagenic actions of N-hydroxy-arylamines formed by CYP1A2. Studies with recombinant human UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A7, UGT1A8, UGT1A9, UGT1A10, UGT2B4, UGT2B7 and UGT2B15 expressed in heterologous cell culture confirmed that UGT1A9 glucuronidated the mutagenic arylamines N-hydroxy-2-acetylaminofluorene (N-hydroxy-2AAF) and 2-hydroxyamino-1-methyl-6-phenylimidazo(4,5-b)pyridine (N-hydroxy-PhIP). To examine the mutagenic potential of these agents, a genotoxicity assay was employed using Salmonella typhimurium NM2009, a bacterial strain expressing the umuC SOS response gene fused to a beta-galactosidase reporter lacZ gene. DNA modification results in the induction of the umuC gene and subsequent enhancement of beta-galactosidase activity. Both N-hydroxy-2AAF and N-hydroxy-PhIP stimulated a dose-dependent increase in bacterial beta-galactosidase activity. In addition, the procarcinogens 2AAF and PhIP were efficiently bioactivated to bacterial mutagens when incubated with Escherichia coli membranes expressing CYP1A2 and NADPH reductase. CYP1A2 generated 2AAF- and PhIP-mediated DNA damage, but only the action of N-hydroxy-2AAF was blocked by expressed UGT1A9. These results indicate that UGT1A9 can control the outcome of a genotoxic response. The results also indicate that while a potential toxicant such as N-hydroxy-PhIP can serve as substrate for glucuronidation, its biological actions can exceed the capacity of the detoxification pathway to prevent the mutagenic episode.
Carcinogenesis 2001 Jun
PMID:The contribution of UDP-glucuronosyltransferase 1A9 on CYP1A2-mediated genotoxicity by aromatic and heterocyclic amines. 1137 3

Most chemical carcinogens require metabolic activation to electrophilic metabolites that are capable of binding to DNA and causing gene mutations. Carcinogen metabolism is carried out by large groups of xenobiotic-metabolizing enzymes that include the phase I cytochromes P450 (P450) and microsomal epoxide hydrolase, and various phase II transferase enzymes. It is extremely important to determine the role P450s play in the carcinogenesis and to establish if they are the rate limiting and critical interface between the chemical and its biological activities. The latter is essential in order to validate the use of rodent models to test safety of chemicals in humans. Since there are marked species differences in expressions and catalytic activities of the multiple P450 forms that activate carcinogens, this validation process becomes especially difficult. To address the role of P450s in whole animal carcinogenesis, mice were produced that lack the P450s known to catalyze carcinogen activation. Mouse lines having disrupted genes encoding the P450s CYP1A2, CYP2E1, and CYP1B1 were developed. Mice lacking expression of microsomal epoxide hydrolase (mEH) and NADPH-quinone oxidoreductase (NQO1) were also made. All of these mice exhibit no gross abnormal phenotypes, suggesting that the xenobiotic-metabolizing enzymes have no critical roles in mammalian development and physiological homeostasis. This explains the occurrence of polymorphisms in xenobiotic-metabolizing enzymes among humans and other mammalian species. However, these null mice do show differences in sensitivities to acute chemical toxicities, thus establishing the importance of xenobiotic metabolism in activation pathways that lead to cell death. Rodent bioassays using null mice and known genotoxic carcinogens should establish whether these enzymes are required for carcinogenesis in an intact animal model. These studies will also provide a framework for the production of transgenic mice and carcinogen bioassay protocols that may be more predictive for identifying the human carcinogens and validate the molecular epidemiological studies ongoing in humans that seek to establish a role for polymorphisms in cancer risk.
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PMID:Understanding the role of xenobiotic-metabolism in chemical carcinogenesis using gene knockout mice. 1137 89

The inhibition and mechanism-based inactivation potencies of phenethyl isothiocyanate (PEITC) for human cytochrome P450 (CYP) activities were investigated using microsomes from baculovirus-infected insect cells expressing specific human CYP isoforms. PEITC competitively inhibited phenacetin O-deethylase activity catalyzed by CYP1A2 (K(i) = 4.5 +/- 1.0 microM) and coumarin 7-hydroxylase activity catalyzed by CYP2A6 (K(i) = 18.2 +/- 2.5 microM). Benzyloxyresorufin O-dealkylase activity catalyzed by CYP2B6 was most strongly and noncompetitively inhibited (K(i) = 1.5 +/- 0.0 microM). Paclitaxel 6alpha-hydroxylase activity catalyzed by CYP2C8 was not affected by PEITC up to 100 microM. PEITC noncompetitively inhibited S-warfarin 7-hydroxylase activity catalyzed by CYP2C9 (K(i) = 6.5 +/- 0.9 microM), S-mephenytoin 4'-hydroxylase activity catalyzed by CYP2C19 (K(i) = 12.0 +/- 3.2 microM), bufuralol 1'-hydroxylase activity catalyzed by CYP2D6 (K(i) = 28.4 +/- 7.9 microM), and chlorzoxazone 6-hydroxylase activity catalyzed by CYP2E1 (K(i) = 21.5 +/- 3.4 microM). The inhibition for testosterone 6beta-hydroxylase activity catalyzed by CYP3A4 was a mixed-type of competitive (K(i) = 34.0 +/- 6.5 microM) and noncompetitive (K(i) = 63.8 +/- 12.5 microM) inhibition. Furthermore, PEITC is a mechanism-based inactivator of human CYP2E1. The k(inact) value was 0.339 min(-1) and K(i) was 9.98 microM. Human CYP1A2, CYP2A6, CYP2B6, CYP2D6, and CYP3A4 were not inactivated. The present study directly proved that the chemopreventive effects of PEITC for nitrosamine-induced carcinogenesis are due to the inhibition of CYP by an in vitro study. The possibility that PEITC would affect the pharmacokinetics of clinically used drugs that are metabolized by these CYP isoforms was also suggested.
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PMID:Inhibition and inactivation of human cytochrome P450 isoforms by phenethyl isothiocyanate. 1145 29

We have previously shown that p53(+/-) knockout mice are highly sensitive to urinary bladder carcinogenesis induced by N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in spite of a lack of effects of p53 heterozygosity on N-butyl-N-(3-carboxypropyl)nitrosamine (BCPN) excretion in urine. To determine the influence of p53 deficiency on in vitro formation of BCPN, mutagenicity of BBN and BCPN and levels of several cytochrome P450 (CYP) isozymes, groups of five p53(+/-) knockout and wild-type mice (littermates), as well as animals of the C57BL/6 parental strain, were administered 0.025% BBN in their drinking water for 4 weeks. The livers and kidneys were then used for analyses of BBN metabolism, western immunoblotting and Ames liquid incubation. BBN treatment caused a slight decrease in BCPN formation in the livers of C57BL/6 mice, but there was no significant difference between p53 knockout, wild-type and C57BL/6 mice. In kidney BCPN formation in p53 knockout mice was 33-46% less than that in their wild-type counterparts. Using anti-rat CYP antibodies, CYP1A2, 2B9/10, 2E1 and 3A11/13 were constitutively detected in liver microsomes and CYP2E1 and 3A11/13 in the kidney. Densitometric determination of these CYP proteins revealed no significant variation in levels detected in both tissues among the four groups of mice. BBN and BCPN were not mutagenic for Salmonella typhimurium TA100 in either the absence or presence of liver S9 from untreated mice and rats and from p53 knockout mice treated with BBN. In conclusion, p53 deficiency and BBN had no enhancing effects on metabolism of BBN to BCPN and expression of the CYP isozymes typically responsible for activation of environmental carcinogens, including both of the N-nitrosamines tested, and their mutagenicity, indicating that the high susceptibility of p53(+/-) knockout mice is not attributable to metabolic activation in liver and kidney by CYP isozymes or urinary excretion of BCPN.
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PMID:Lack of change in the levels of liver and kidney cytochrome P-450 isozymes in p53+/- knockout mice treated with N-butyl-N-(4-hydroxybutyl)nitrosamine. 1150 36

The consumption of cooked meat appears to predispose individuals to colonic cancer and heterocyclic aromatic amines (HA), formed during the cooking of meat, have been suggested as aetiological agents. Consumption of cruciferous vegetables is thought to protect against cancer. To study the effect of cruciferous vegetables on heterocyclic aromatic amine metabolism in man, a three-period, dietary intervention study has been carried out with 20 non-smoking Caucasian male subjects consuming cooked meat meals containing known amounts of these carcinogens. A high cruciferous vegetable diet (250 g each of Brussels sprouts and broccoli per day) was maintained during period 2 but such vegetables were excluded from periods 1 and 3. At the end of each period, subjects consumed a cooked meat meal and urinary excretion of the HA 2-amino-3,8-dimethylimidazo(4,5-f)quinoxaline (MeIQx) and 2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine (PhIP) was measured. Following a 12 day period of cruciferous vegetable consumption (period 2), induction of hepatic CYP1A2 activity was apparent from changes in the kinetics of caffeine metabolism. Excretion of MeIQx and PhIP in urine at the end of this period of the study was reduced by 23 and 21%, respectively, compared with period 1. This reduction in excretion is probably due to an increase in amine metabolism that might be expected given the observed increase in CYP1A2 activity, since this enzyme has been shown to be primarily responsible for the oxidative activation of MeIQx and PhIP in man. In period 2, urinary mutagenicity was increased relative to period 1 by 52 and 64% in the absence and presence, respectively, of a human liver microsomal activation system, yet no evidence was found of PhIP adduction to lymphocyte DNA, a potential biomarker of the activation process. After another 12 days without cruciferous vegetables (period 3 of the study), the kinetics of caffeine metabolism had returned to original values but excretion of MeIQx and PhIP was still reduced by 17 and 30%, respectively, and urinary mutagenicity (with metabolic activation) was still elevated compared with period 1. This prolonged response of amine metabolism to the cruciferous vegetable diet, shown especially with PhIP, suggests that enzyme systems other than CYP1A2 are involved and affected by a cruciferous vegetable diet.
Carcinogenesis 2001 Sep
PMID:Effect of cruciferous vegetable consumption on heterocyclic aromatic amine metabolism in man. 1153 63

The steady-state kinetics and specific activity of 2-, 4-, and 16alpha-hydroxylation of 17beta-estradiol (E(2)) were evaluated for human cytochrome P450 (CYP) 1A1, 1A2, 1B1, and 3A4 enzymes, using complementary DNA-expressed CYP isoforms. CYP1A2 showed the highest 2-hydroxylation activity, followed by CYP1A1, 1B1, and 3A4. CYP1B1 had the highest 4-hydroxylation activity, followed by CYP1A2, 1A1, and 3A4. The 16alpha-hydroxylation reaction was catalyzed mainly by CYP1A2 and, to a similar, slightly lower extent, CYP3A4 and 1A1, with a lesser contribution by CYP1B1. The E(2) 2-, 4-, and 16alpha-hydroxylation activities of human liver microsomes were 1.3 +/- 0.3, 0.5 +/- 0.06, and 0.3 +/- 0.05 nmol metabolite/min/nmol P450, respectively. The contribution of CYP1A1 and 1B1 (mainly extrahepatic) to the E(2) hydroxylation reactions, relative to CYP1A2 and 3A4 (predominantly hepatic), may be relevant to understanding the process of hormonal carcinogenesis both in liver and in extrahepatic tissues.
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PMID:Role of human cytochrome P450 1A1, 1A2, 1B1, and 3A4 in the 2-, 4-, and 16alpha-hydroxylation of 17beta-estradiol. 1155 28

Allyl sulfides such as diallyl sulfide (DAS), diallyl disulfide (DADS), and diallyl trisulfide (DATS), typical flavor components of Allium vegetables, have been shown to inhibit benzo[a]pyrene (B[a]P)-induced carcinogenesis in animal models. As a possible mechanism of this inhibition, the effect of these volatile substances on cytochrome P450 (CYP)1 (CYP1A1, 1A2 and 1B1)-mediated bioactivation of B[a]P was investigated using a human hepatoma cell model (HepG2). DADS and DATS inhibited the B[a]P-induced ethoxyresorufin O-deethylase (EROD) activity, a marker enzyme for CYP1, by 30-90% and 70-95% at 100-1,000 microM concentration, respectively. The cell viability, an indicator of the capacity to inhibit B[a]P bioactivation, was increased by treatments of 100-1,000 microM DADS and 10-100 microM DATS. Immunoblot results indicated that the B[a]P inducible CYP1A2 protein was suppressed by 100-1,000 microM of DADS and 10-100 microM of DATS, but CYP1A1 and 1B1 were not detectable in any microsomes. Analysis of B[a]P metabolites revealed that the level of 7,8-diol formed was significantly reduced in the DADS and DATS treated microsomes as compared to the control. The level of 9,10-diol and 4,5-diol formed was also lowered by the allyl sulfide treatments. These results suggest that the protective mechanism of allyl sulfides on B[a]P-induced carcinogenesis is possibly related with the modulation of CYP1-mediated bioactivation of B[a]P.
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PMID:Modulation of cytochrome P4501-mediated bioactivation of benzo[a]pyrene by volatile allyl sulfides in human hepatoma cells. 1175 11


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