P450 Genes: Evolution, Regulation, and Relationship To Human Cancer and Pharmacogenetics

Gonzalez, F J; Jaiswal, Amit; Nebert, Daniel W.

doi:10.1101/sqb.1986.051.01.101

Cited by 31 publications

(15 citation statements)

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“…Phase I mono-oxygenation Phase I mono-oxygenation is performed by the cytochrome P-450 microsomal enzyme system, present in many tissues including lung (Gonzalez et al, 1986). (The colour in the cell that the name implies is imparted by haeme, a pigment (P) with peak optical absorption wavelength of 450 nm.)…”

Section: Metabolism Offoreign Chemicals (Including Potential Carcinogmentioning

confidence: 99%

Genetic predisposition to lung cancer

1990

Br J Cancer

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In Britain, the life-time risk of lung cancer in men who smoke 20 or more cigarettes per day is about 15%. That most smokers never develop lung cancer has promoted interest in the role of host factors. While chance, other environmental factors and the competing effect of other diseases, some of which are also smoking related, are all likely to affect individual lung cancer risk, genetic factors may also be important. This review examines the evidence for genetic predisposition to smoking related lung cancer.The review concentrates on the numerous metabolic studies that have sought differences between individuals in the genetic control of biochemical pathways that could be involved in the metabolism of carcinogens in tobacco smoke. Insights gained are likely to have wider implications for other environmental carcinogens. Other studies that have sought simple evidence, such as familial clustering or associations of lung cancer with blood group, HLA and other naturally occurring antigens, are also examined. The field of chromosomal abnormalities in lung cancer and the difficulties in interpreting them is reviewed only briefly, since this area may not directly relate to tobacco smoking and has been reviewed elsewhere (Birrer & Minna, 1988). Various sources of bias important in the interpretation of the metabolic studies in particular are outlined. Future research is likely to be dominated by the recent advances in molecular genetics that offer the possibility of circumventing bias by the direct identification of genes, but at present this is possible only to a limited extent. Familial clustering of lung cancer casesFamilial clustering of a cancer (or indeed of any disease) is an insensitive indicator of genetic predisposition. Peto (1980) and Bodmer (1986) have pointed out that a cancer can have a major genetic component yet show no detectable familial clustering. The ratio of the incidence of the cancer in relatives of known cases to that in age-matched controls is the only measure of familial clustering (in the absence of a marker). This ratio will be much smaller than the ratio of the incidence in genetically susceptible to non-susceptible individuals, which is the direct measure of the magnitude of the genetic effect. It is a question of dilution -not all patients with cancer will be genetically susceptible individuals, fewer of their relatives will be, and tne general population contains susceptibles as well as non-susceptibles. (1980) showed that even with a very large cancer risk in susceptibles, the incidence of cancer in relatives will generally be increased by no more than 1.5-3-fold. It is difficult in a family study to show that such a modest increase could not be due to chance, shared exposure or other bias.Five studies have examined lung cancer incidence in relatives of cases, but three (Tokuhata & Lilienfeld, 1963b;

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Section: Metabolism Offoreign Chemicals (Including Potential Carcinogmentioning

confidence: 99%

Genetic predisposition to lung cancer

1990

Br J Cancer

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“…The protein product of the CYPlAl gene exhibits aryl hydrocarbon (Ah) hydroxylase activity, and is involved in both detoxification as well as the conversion of certain xenobiotics to active carcinogens. In the human population, one out of ten individuals exhibits a high Ah-hydroxylase-inducible phenotype [2], which is believed to be associated with an increased risk of smoking-related cancers [3 -51. More recently, an increased level of Ah hydroxylase activity in mammary carcinoma tissue has been associated with a poor prognosis [6].…”

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confidence: 99%

Differences in 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin‐inducible CYP1A1 expression in human breast carcinoma cell lines involve altered trans‐acting factors

Thomsen

Nissen

Stacey

et al. 1991

European Journal of Biochemistry

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Differences in expression of the CYPIAI gene have previously been observed in human breast carcinoma cell lines exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Using an expression vector containing the functional 5'-regulatory region of human CYPIAI (up to -1140) fused to the reporter gene CAT (for chloramphenicol acetyltransferase), the breast carcinoma cell lines, MCF-7, T47-D and ZR-75-1, classified as highly responsive to TCDD, were highly responsive to TCDD in the chloramphenicol acetyltransferase assay as well. Gel mobility shift assays have shown that these cell lines express a nuclear protein that binds the aryl hydrocarbon (Ah) receptor responsive element. The low or non-responsive cell lines, AL-1, BT-20 and CAMA-1, were low or non-responsive to TCDD in the chloramphenicol acetyltransferase assay, suggesting that the low-responsive phenotype is caused by altered trans-acting factors. However, the mechanism appears to differ among the cell lines. Whereas no induction was observed in AL-1, a fivefold induction in activity was observed in BT-20 and CAMA-1. The TCDD concentration giving half-maximum induction differed greatly between CAMA-1 and BT-20. The gel mobility shift assay showed the presence of a protein that bound specifically to the Ah responsive element in the nonresponsive cell line AL-1, as well as the low-responsive cell lines, BT-20 and CAMA-1. The high basal activity but low induction observed in CAMA-1 may be due to an Ah receptor constitutively bound to the Ah responsive element.The cytochrome P450 enzymes have been divided into 14 families, of which 9 are present in mammals [l]. The CYPIA family consists of the two genes, CYPIAI and CYPIA2. The protein product of the CYPlAl gene exhibits aryl hydrocarbon (Ah) hydroxylase activity, and is involved in both detoxification as well as the conversion of certain xenobiotics to active carcinogens. In the human population, one out of ten individuals exhibits a high Ah-hydroxylase-inducible phenotype [2], which is believed to be associated with an increased risk of smoking-related cancers [3 -51. More recently, an increased level of Ah hydroxylase activity in mammary carcinoma tissue has been associated with a poor prognosis [6].The expression of Ah hydroxylase is regulated mainly at the level of CYPIAI transcription [7]. The gene is induced by planar polycyclic aromatic hydrocarbons and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), while no endogenous inducer has yet been identified [8, 91. Inducers mediate their effect by binding to a trans-acting factor, i.e. the aryl hydrocarbon receptor. The Ah receptor has not been purified or cloned, but is proposed to be a member of the steroid hormone receptor superfamily [8], due to both mechanistic as well as physico-chemical similarities [lo, 111. Like the glucocorticoid receptor, the Ah receptor is an 8 -9-S heteromeric complex [Ill and is transformed to a 4-5-S form by dissociation of the heat-shock protein 90 (hsp90) upon binding of ligand and translocation. In contrast to the hsp90-associated...

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“…This deficiency is inherited as an autosomal recessive trait and appears to result from one of several mutations in the gene coding for a single liver cytochrome P-450 (P-4501ID gene family) (4,5). Patients with this defective cytochrome are at risk for adverse reactions to many medications (6), and may have altered risks for developing illnesses such as Parkinson's disease (7) and some cancers (1). At least eight other human liver cytochromes P-450 have now been identified (8,9).…”

Section: Introductionmentioning

confidence: 99%

“…Reactions catalyzed by cytochromes P-450 often produce metabolites less bioactive and more readily eliminated than are the parent compounds. However, reactions catalyzed by these enzymes have also been implicated in pathological processes including carcinogenesis, mutagenesis, cytotoxicity, and teratogenesis (1). To date, there have been at least 21 cytochromes P-450 purified from rat liver, each with characteristic structure, substrate binding affinities, and in some cases, differential regulatory responses to drugs or other xenobiotics (2).…”

Section: Introductionmentioning

confidence: 99%

Erythromycin breath test as an assay of glucocorticoid-inducible liver cytochromes P-450. Studies in rats and patients.

et al. 1989

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The major P450IIIA gene family member present in human liver is HLp which, like its rat liver orthologue P450p, is inducible by glucocorticoids and catalyzes erythromycin N-demethylation. To develop a practical method to estimate the amounts of HLp in patients ['4(CN-methyl erythromycin was injected into rats that had been pretreated with dexamethasone or with inducers of other forms of cytochrome P450. The rate of demethylation of this substrate, measured simply as "'CO2 in the breath, correlated well with the concentrations of immunoreactive P450p protein (r = 0.70), holocytochrome P450p (r = 0.70), or with erythromycin N-demethylase activity (r = 0.90) determined in the liver microsomes prepared from each rat. Next, ["'CJN-methyl erythromycin was administered to 30 patients and there was a sixfold interindividual variation in breath 14CO2 production seemingly unrelated to medications, smoking status or age. However, the average breath test values were twofold greater in female as compared to male patients (P < 0.01). Breath "'CO2 production rose in patients retested after treatment with the P450111A inducers dexamethasone (P < 0.05) or rifampicin (P < 0.05) and was decreased after treatment with the HLp inhibitor triacetyloleandomycin (P < 0.05). We conclude that the erythromycin breath test provides a convenient assay of P450IIIA cytochromes in rats and in some patients.

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P450 Genes: Evolution, Regulation, and Relationship To Human Cancer and Pharmacogenetics

Cited by 31 publications

References 0 publications

Genetic predisposition to lung cancer

Genetic predisposition to lung cancer

Differences in 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin‐inducible CYP1A1 expression in human breast carcinoma cell lines involve altered trans‐acting factors

Erythromycin breath test as an assay of glucocorticoid-inducible liver cytochromes P-450. Studies in rats and patients.

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