Questionable Relation of Aryl Hydrocarbon Hydroxylase to Lung-Cancer Risk

Paigen, Beverly; Gurtoo, Hira L.; Minowada, Jun; Houten, Lorne; Vincent, Ronald G.; Paigen, Kenneth; Parker, N; Ward, Elizabeth; Hayner, Nancy Thompson

doi:10.1056/nejm197708182970702

Cited by 122 publications

(26 citation statements)

References 6 publications

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“…1 (33,34). However, the latter studies have not been confirmed in twin and lung cancer patients (35)(36)(37), and the questions raised by the latter studies remain unanswered (38) the inhibitory effects of MAb 1-7-1, indicating that AHHase and ECDEtase in monocytes are catalyzed by a P-450 different from the MAb 1-7-1 sensitive P450 of human placenta and lymphocytes. In a previous study (39), we reported that polyclonal rabbit antibodies to rat liver MC-P-450 inhibited both BaA-induced lymphocytes and monocytes.…”

Section: Resultsmentioning

confidence: 99%

Phenotyping of cytochromes P -450 in human tissues with monoclonal antibodies

Fujino

Park

West

et al. 1982

Proc. Natl. Acad. Sci. U.S.A.

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Cytochrome P450 (P450)-dependent aryl hydrocarbon hydroxylase (AHHase) and 7-ethoxycoumarin deethylase (ECDEtase) in human tissues were differentially inhibited by monoclonal antibodies (MAbs) that were prepared to inhibit and completely inhibited the activity of3-methylcholanthrene-induced rat liver P-450. The AHHase and ECDEtase of placentas from individual women who smoked were inhibited by the MAbs by 83-90% and by 34-74%, respectively. Benz [a]anthracene (BaA)-induced AHHase and ECDEtase in lymphocytes were inhibited 18-65% and 30-78%, respectively. The enzymes in both control and BaA-induced human cells in culture were inhibited to different extents. Both the AHHase and ECDEtase in control and BaAinduced monocytes and in normal liver were largely unaffected by the MAb. Thus, we have with the MAbs: (i) identified P-450s with a common antigenic site in placenta, lymphocytes, and human cells in culture; (ii) identified two forms of hydrocarbon-induced P450s in lymphocytes, at least one of which is common with the induced P450s of placenta and with a P-450 form present in uninduced lymphocytes; (iii) identified two forms of P-450 responsible for smoking-induced ECDEtase activity in placenta, one of which is also responsible for AHHase activity; (iv) shown that the P-450s of liver, basal, and BaA-induced monocytes are different from the MAb-sensitive P-450s of placenta and lymphocytes; (v) quantitated in several human tissues the percentages of control and inducible AHHase and ECDEtase that are dependent on the MAb-sensitive P-450; and (vi) defined by HPLC the contribution of the MAb-sensitive P-450 to the formation of specific benzo[a]-pyrene metabolites. The results demonstrate the value of MAbs for defining antigenic site relatedness for different enzymatic functions ofP450s and for identifying and quantifying the amount of a specific enzyme activity in a tissue dependent on specific P450s. This study may be a prototype for the use of MAbs for phenotyping and mapping of P-450s responsible for specific metabolic reactions and, thus, may be useful in determining the relationship of P450 phenotype to individual differences in drug metabolism and carcinogen susceptibility.The mixed-function oxidases containing cytochromes P450 metabolize a variety ofxenobiotics and endogenous compounds, including carcinogens, drugs, and steroids (1, 2). The P-450s govern reactions that lead to detoxified metabolites or to toxic, mutagenic, and carcinogenic compounds (1, 2). The P-450s convert benzo[a]pyrene (BaP) to an active form that is covalently bound to DNA (3). The latter system activates xenobiotics to their mutagenic forms in the Ames assay (4). Xenobiotic activation and detoxification may occur through alternative metabolic pathways regulated by different P-450s with overlapping specificities. Thus, BaP is converted by P-450s and linked enzymes, to >40 metabolites (1). BaP metabolism resulting in activation involves P450-catalyzed epoxidation, followed by formation of (-)-trans-7,8-dihydroxy-7,8-dihydrobenzo[...

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Section: Resultsmentioning

confidence: 99%

Phenotyping of cytochromes P -450 in human tissues with monoclonal antibodies

Fujino

Park

West

et al. 1982

Proc. Natl. Acad. Sci. U.S.A.

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“…Activity was expressed as picomoles metabolites formed in 16 h/pg DNA. DNA was measured according to the method described by Paigen et al (25). Cells harvested from individual umbilical veins were incubated for 16 h in order to get sufficient reaction products to avoid having to pool cells from different individuals in order to detect activity.…”

Section: Methodsmentioning

confidence: 99%

Maternal Smoking Increases Xenobiotic Metabolism in Placenta but Not Umbilical Vein Endothelium

1984

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umbilical vein endothelium from these same pregnancies was unaffected by maternal smoking and remained low. In order to confirm that AHH present in endothelium was inducible, we also demonstrated dose-dependent increases in AHH activity in primary cultures of human umbilical vein endothelial cells exposed to PAHs. These findings may indicate first pass protection of the fetus by placental xenobiotic metabolism, or that endogenous factors suppress AHH induction in the fetus but not placenta. may contribute to the development of certain birth defects (4,16,17). Although complex mixtures of chemicals contained in cigarette smoke have been described, little is known about the mechanisms by which these compounds may be embryopathic or about how the human conceptus can be protected from such chemical toxicity.In order to approach these problems, we have been studying the effects of maternal smoking on xenobiotic metabolism in human placenta, concentrating on AHH, a cytochrome P-450 monooxygenase system which increases its activity when mothers smoke (14,20,24,29,30). AHH catalyzes the first step in the metabolism of several of the toxins absorbed from cigarette smoke including PAHs. These compounds, which are concentrated in cigarette smoke, have been found to be carcinogenic, mutagenic, and teratogenic in animals (5). The consequences of increased placental AHH activity in response to maternal smoking are unknown. On the one hand, microsomes from placentas from smokers have been shown to metabolize certain PAHs to mutagenic products in vitro (15). On the other hand, AHH participates in the clearance of toxins such as PAHs in vivo (18,23), and increased placental activity may reduce levels of toxic PAHs in fetal tissues. Hence, increased placental AHH, coupled with a toxic load of PAHs from maternal smoking, could theoretically protect or endanger the developing fetus.Because we are unable to measure placental clearance of PAHs directly in humans, we decided to approach the question of the role of placental PAH metabolism indirectly by comparing effects of cigarette smoking on placenta and a fetal tissue immediately distal to it, umbilical vein endothelium. We hypothesized that if increased placental AHH activity were involved in effectively decreasing levels of PAHs in distal tissues, then we would expect distal tissues to be less affected than the placenta by maternal cigarette smoke. We used AHH activity itself as a measure of PAH exposures and measured activity in placentas and umbilical vein endothelium from smoking and nonsmoking women. We report that while AHH activity in placenta is markedly increased by maternal cigarette smoking, activity in umbilical vein endothelium is not. MATERIALS AND METHODSProcurement of tissues. Placentas were collected at the time of delivery. Several representative samples of villous tissue were immediately removed and frozen at -70" C. Umbilical cords were removed and refrigerated no longer than 8 h prior to use. Cords were used only if they contained untraumatized segments greate...

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“…The first reports on AHH and broncho genic carcinoma in man could initially not be confirmed [6], but more recent studies con sidering the importance of blast transforma tion in lymphocyte test systems [7][8][9] have verified the feasibility of this method.…”

Section: Introductionmentioning

confidence: 99%

Oral and Oropharyngeal Cancer, Aryl Hydrocarbon Hydroxylase Inducibility and Smoking

Andréasson¹,

Björlin²,

Laurell

et al. 1985

ORL

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In a series of 50 consecutive cases with oral or oropharyngeal malignancies, aryl hydrocarbon hydroxylase (AHH) inducibility and smoking habits were studied. 82% of the patients were smokers. The AHH levels were divided into high, intermediate and low groups and were correlated to a healthy control material also divided into the groups mentioned. A significant overrepresentation of patients with a high AHH level (p < 0.0005) as well as an underrepresentation of low AHH levels (p < 0.01) was found. Smokers with a high AHH level run a sixfold risk of developing cancer in this area and develop it earlier in life than people with low or intermediate AHH levels. Recurrences or secondary malignancies in the upper digestive tract or airways were substantially higher in the high AHH level group as compared to the other. A high AHH inducibility level thus is of both pathogenetic as well as prognostic importance in oral and/or oropharyngeal cancer.

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Questionable Relation of Aryl Hydrocarbon Hydroxylase to Lung-Cancer Risk

Cited by 122 publications

References 6 publications

Phenotyping of cytochromes P -450 in human tissues with monoclonal antibodies

Phenotyping of cytochromes P -450 in human tissues with monoclonal antibodies

Maternal Smoking Increases Xenobiotic Metabolism in Placenta but Not Umbilical Vein Endothelium

Oral and Oropharyngeal Cancer, Aryl Hydrocarbon Hydroxylase Inducibility and Smoking

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