Metabolism of polycyclic aromatic hydrocarbons in cultured human leukocytes under genetic control

Kellermann, Gottfried; Luyten-Kellermann, Mieke; Shaw, Charles R.

doi:10.1007/bf00385737

Cited by 27 publications

(13 citation statements)

References 25 publications

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“…Fig. 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.…”

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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“…The genetic control of aryl hydrocarbon hydroxylase in human cells and tissues is also uncertain. Induction of aryl hydrocarbon hydroxylase by 3methylcholanthrane has been studied in cultured human lymphocytes (14). In this study of 353 healthy individuals, both constitutive and 3-methylcholanthraneinduced levels of aryl hydrocarbon hydroxylase were measured.…”

Section: Interindividual Variation In Binding Of Benzo[a]pyrene To Dnmentioning

confidence: 99%

Interindividual Variation in Binding of Benzo[ a ]pyrene to DNA in Cultured Human Bronchi

Harris

Autrup

Connor

et al. 1976

Science

131

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The binding of benzo[ a ]pyrene to DNA in cultured human bronchus was measured in specimens from 37 patients. The binding values ranged from 2 to 151 picomoles of benzo[ a ]pyrene per milligram of DNA with an overall mean ± standard error of 34.2 ± 5.2. This 75-fold interindividual variation in the binding of benzo[ a ]pyrene to DNA is similar in magnitude to that found in pharmacogenetic studies of drug metabolism. Aryl hydrocarbon hydroxylase is also inducible by benz[ a ]anthracene in the bronchial mucosa.

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“…Following reports of the mouse high affinity/low affinity AHR paradigm and relationship of high CYP1 inducibility and cancer (12), a CYP1 inducibility assay was developed in mitogen-activated PAH-treated human lymphocytes (which are transformed 55 h later into lymphoblasts) in culture (13), and an association was shown between high CYP1 inducibility and bronchogenic carcinoma (14). Following improvements in the assay (15), many laboratories have found that the distribution of CYP1 inducibility was generally skewed to the left (Fig.…”

Section: Pah-induced Cyp1 and Cancer Studies In Humansmentioning

confidence: 99%

Role of Aryl Hydrocarbon Receptor-mediated Induction of the CYP1 Enzymes in Environmental Toxicity and Cancer

Nebert

Dalton

Okey

et al. 2004

Journal of Biological Chemistry

1,050

731

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The mammalian CYP1A1, CYP1A2, and CYP1B1 genes (encoding cytochromes P450 1A1, 1A2, and 1B1, respectively) are regulated by the aromatic hydrocarbon receptor (AHR). The CYP1 enzymes are responsible for both metabolically activating and detoxifying numerous polycyclic aromatic hydrocarbons (PAHs) and aromatic amines present in combustion products. Many substrates for CYP1 enzymes are AHR ligands. Differences in AHR affinity between inbred mouse strains reflect variations in CYP1 inducibility and clearly have been shown to be associated with differences in risk of toxicity or cancer caused by PAHs and arylamines. Variability in the human AHR affinity exists, but differences in human risk of toxicity or cancer related to AHR activation remain unproven. Mouse lines having one or another of the Cyp1 genes disrupted have shown paradoxical effects; in the test tube or in cell culture these enzymes show metabolic activation of PAHs or arylamines, whereas in the intact animal these enzymes are sometimes more important in the role of detoxification than metabolic potentiation. Intact animal data contradict pharmaceutical company policies that routinely test drugs under development; if a candidate drug shows CYP1 inducibility, further testing is generally discontinued for fear of possible toxic or carcinogenic effects. In the future, use of "humanized" mouse lines, containing a human AHR or CYP1 allele in place of the orthologous mouse gene, is one likely approach to show that the AHR and the CYP1 enzymes in human behave similarly to that in mouse.Classical cancer studies in the 1930s showed that coal tar applied to a rabbit's ear causes papillomas followed by tumors. The active ingredients in coal tar were determined to be polycyclic aromatic hydrocarbons (PAHs) 1 such as benzo [a]pyrene (BaP). The parent PAH at first was thought to be the carcinogen and an enzyme that metabolized PAHs thought to be beneficial in detoxification (1). It was subsequently shown that PAHs, metabolized to reactive intermediates, bind covalently to nucleic acids and proteins to form adducts (2); thus, the concept of "metabolic activation" by PAH-metabolizing enzymes was born.Mammalian cell cultures were found to have BaP hydroxylase (aryl hydrocarbon hydroxylase) activity that becomes highly induced within 12-24 h upon exposure to various PAHs (3). This paradigm for studying the response of cultured cells to PAH treatment has led to a wealth of knowledge concerning transcription, translation, and signal transduction pathways (4 -6).Some inbred mouse strains are "sensitive" to the PAH inducer, whereas others are not (7). Breeding sensitive C57BL/6 (B6) with resistant DBA/2 (D2) mice revealed that resistance was inherited largely as an autosomal recessive trait (8). When 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; dioxin) was realized to be at least 30,000 times more potent than PAHs as an inducer of BaP hydroxylase, B6 and D2 mice were treated with dioxin, and the effective dose for 50% induction (ED 50 ) was shifted ϳ15-fold to the right in the ...

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Metabolism of polycyclic aromatic hydrocarbons in cultured human leukocytes under genetic control

Cited by 27 publications

References 25 publications

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

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

Interindividual Variation in Binding of Benzo[ a ]pyrene to DNA in Cultured Human Bronchi

Role of Aryl Hydrocarbon Receptor-mediated Induction of the CYP1 Enzymes in Environmental Toxicity and Cancer

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