Cigarette Smoking: Stimulatory Effect on Metabolism of 3,4-Benzpyrene by Enzymes in Human Placenta

Welch, R. M.; Harrison, Y. E.; Conney, Allan H.; Poppers, Paul J.; Finster, Mieczyslaw

doi:10.1126/science.160.3827.541

Cited by 185 publications

(59 citation statements)

References 8 publications

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“…1) (11). This finding is similar to the effects of smoking on human placental AHH activity (12)(13)(14). Since the AHH assay measures chiefly the formation ofbenzo[a]pyrene (BaP)-phenols, BaP metabolism in vitro was studied further by quantifying specific metabolites by high pressure liquid chromatography (HPLC) (11).…”

Section: Placental Metabolismsupporting

confidence: 88%

Placental markers of human exposure to polychlorinated biphenyls and polychlorinated dibenzofurans.

Lucier

Nelson

Everson

et al. 1987

Environ Health Perspect

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Our studies have evaluated biochemical changes in placentae from humans exposed to rice oil contaminated with polychlorinated biphenyls (PCBs) and polychlorinated dibenzofurans (PCDFs) in Taiwan. Placentae were obtained from nonsmoking women 4 to 5 years after the exposure had occurred. The exposed individuals ingested approximately 1 to 3 g PCBs and 5 mg PCDFs, and many exhibited symptoms characteristic of PCB poisoning. This disease was termed "Yu-Cheng" in Chinese. Based on data from experimental animal models, we examined a number of parameters in placentae from control and exposed women, including arylhydrocarbon hydroxylase (AHH) activity, cytochrome P450 isozymes, epidermal growth factor (EGF) receptor binding properties and actions, and Ah receptor. We also quantified concentrations of various PCB and PCDF congeners known to be present in the contaminated rice oil. Our results revealed a dramatic elevation in placental AHH activity in samples from PCB/PCDF-exposed women. This increase in enzyme activity was associated with a parallel increase in placental microsomal protein immunochemically related to cytochrome P-450 form 6 [derived from 2,3,7,8-tetrachlorodibenzop-dioxin (TCDD)-induced rabbit lung]. No other cytochrome P-450 isozyme was detected in placental preparations, and the form 6 homolog was found only in placentae from exposed women. EGF receptormediated autophosphorylation capacity was significantly diminished in PCB/PCDF placentae, but this effect was not associated with changes in plasma membrane EGF receptor binding properties (Kd and Bm,). The EGF receptor autophosphorylation effect correlated well with the decrease in birth weight observed in offspring of exposed women, suggesting that this biochemical event might provide a good marker of effect for the toxic halogenated aromatics. Two PCDF congeners (2,3,4,7,2,3,4,7, were detected in Yu-Cheng placentae but not controls. Several PCBs were also detected (including the 2,2',4,4',5,5'-hexa-CB and 2,3,3',4,4',5-hexaCB) in much higher concentrations in Yu-Cheng placentae. Surprisingly, placental concentrations of PCBs correlated better with effects than did the PCDFs. Our findings are discussed in relation to the risk assessment process.

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Section: Placental Metabolismsupporting

confidence: 88%

Placental markers of human exposure to polychlorinated biphenyls and polychlorinated dibenzofurans.

Lucier

Nelson

Everson

et al. 1987

Environ Health Perspect

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“…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.…”

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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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“…Since antipyrine is cleared almost entirely by hepatic biotransformation (Brodie and Axelrod, 1950), it seems likely that accelerated elimination of this drug is due to induction of the hepatic mixed function oxidases involved in drug metabolism. Previous studies in humans have shown that cigarette smoking is associated with increased activity of these enzymes in the placenta (Welch et al, 1968) and pulmonary alveolar macrophages (Cantrell et al, 1973).…”

Section: Introductionmentioning

confidence: 95%

Alterations of Drug Metabolism in Rats Exposed to Cigarette Smoke

Farrell

Cash

et al. 1980

Aust J Exp Biol Med

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Summary. In male rats exposed to cigarette smoke, antipyrine clearance was enhanced to the same extent as has been observed in human cigarette smokers. The activity of ary 1 hydrocarbon hydroxylase, a representative microsomal mixed function oxidase, was increased significantly in lung and kidney of smoke-exposed rats compared with controls. The activity of this enzyme in the liver, however, was not altered by cigarette smoke. Although aryl hydrocarbon hydroxylase activity in extrahepatic tissues was significantly enhanced afler cigarette smoke exposure, the total drug metabolizing capacity of these tissues remained trivial compared with that of the liver. Hence, extrahepatic drug metabolism is unlikely to account for enhanced antipyrine elimination in cigarette smokers. The present study has established an animal model for studying the changes produced by cigarette smoke which result in enhanced drug metabolism in man.

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Cigarette Smoking: Stimulatory Effect on Metabolism of 3,4-Benzpyrene by Enzymes in Human Placenta

Cited by 185 publications

References 8 publications

Placental markers of human exposure to polychlorinated biphenyls and polychlorinated dibenzofurans.

Placental markers of human exposure to polychlorinated biphenyls and polychlorinated dibenzofurans.

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

Alterations of Drug Metabolism in Rats Exposed to Cigarette Smoke

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