ISSN:0960-314X    

出版商:OVID    

年代:1991

数据来源: OVID

ISSN:0960-314X    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

The polymorphism of mammalian aromatic hydrocarbon (Ah) responsiveness appears to be correlated with genetic differences in risk of bronchogenic carcinoma caused by cigarette smoking. The human polymorphism has been uncovered, largely as the result of corresponding genetic differences characterized first in the mouse. The murine Ah locus has been defined as the gene encoding the aromatic hydrocarbon-responsive (Ah) receptor, responsible for the inducibility of a battery of at least six genes, two of which encode P450 enzymes. The high-affinity receptor and, hence, more highly induced levels of P450, can result in greater concentrations of polycyclic aromatic reactive intermediates that form DNA adducts and, ultimately, mutation fixation (tumour initiation). The Ah receptor is also likely to participate in growth and differentiation signal transduction pathways (tumour promotion).Positive and negative control regions flanking the murine Cyp 1a-1 and human CYP 1A1 (cytochrome P1 450) genes have been identified. A DNA motif approximately 1 kb upstream of the transcription start site appears to affect the translatability of the CYP1A1 mRNA and activity of the enzyme. Expression of the CYP1A1 or CYP1A2 enzyme in mouse hepatoma Hepa-1 cells lacking endogenous CYP1A1 activity represses constitutive transcription of not only the endogenous Cypla-1 gene but other genes in the dioxin-inducible [Ah] battery.Human polymorphisms involving a Msp I site 450 bp downstream from the last CYP 1A1 exon have been described in Japan, the Eastern Mediterranean, Norway and the USA. The ‘1.9 allele’ is associated with an increased incidence of Kreyberg Type I bronchogenic carcinomas in Japan and has recently been correlated with a valine-to-isoleucine substitution at position 462 in the haeme-binding region. This allele is about 3 times more frequent in Japan than in Caucasians of Norway and the USA, in which no correlation has been found between this allele and lung cancer. More work is needed to clarify these findings. Isolation and sequencing of the human Ah receptor cDNA, and the subsequent screening of populations for polymorphisms, hold great promise for predicting interindividual risk of cancer caused by smoking and other environmental pollutants.

ISSN:0960-314X    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

Aflatoxin is believed to be a major causative agent in the high incidence of primary liver cancer seen in certain regions of the world. In Fujian Province, an aflatoxin-endemic region of China, we compared the cigarette smoking habits of 200 primary hepatoma patients with those of 200 matched nonhepatoma controls. We excluded from our study all individuals with evidence of hepatitis B virus serum antigen and/or alcoholic cirrhosis. Interestingly, two groups of hepatoma patients could be discerned. In patients more than 50 years of age, a significantly higher number of cases of primary hepatoma was found among nonsmokers than smokers (odds ratio = 2.06; 95% confidence interval = 1.32-3.20). In patients less than 50 years of age, this difference was not seen. Previous studies in the rat, mouse and duck had suggested that agents present in cigarette smoke might induce a cytochrome P450-mediated detoxication pathway, leading to protection against aflatoxin-induced primary liver cancer. Our clinical data in the present study are therefore consistent with the previous laboratory animal experiments.

ISSN:0960-314X    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

Simultaneous expression plasmids were constructed for bovine adrenal cytochromes P450cl7 and P450c21 (pAγα) and for both P450s together with NADPH-cytochrome P450 reductase (pARγα). On introduction of each of the plasmids into Saccharomyces cerevisiae AH22 cells, the transformed yeast strains AH22/pAγα and AH22/pARγα produced about 105molecules per cell of P450cl7 and 2 x 103molecules per cell of P450c21. The expression levels of NADPH-cytochrome P450 reductase was about 3 X 104and 6 X 105molecules per cell in the strains AH22/pAγα and AH22/pARγα, respectively. When progesterone was added to growing cell cultures of the transformed yeast strains, the substrate was metabolized more rapidly in the AH22/pARγα cells than AH22/pAγα cells, probably due to overproduction of the reductase. In the AH22/pARγα cells, progesterone was first converted into 17a-hydroxyprogesterone to the extent of 82% by the catalysis of P450cl7. 17α-hydroxyprogesterone was further converted into 11-deoxycortisol by P450c21 to the extent of 60% of the added substrate. The conversion of progesterone into androstenedione through 17α-hydroxyprogesterone was estimated to be less than 3% suggesting very low C17.20-lyase activity of P450cl7, although other hydroxylation products were detected. Androstenedione was further converted into testosterone by an unknown pathway present in S. cerevisiae cells.

ISSN:0960-314X    

出版商:OVID    

年代:1991

数据来源: OVID

ISSN:0960-314X    

出版商:OVID    

年代:1991

数据来源: OVID

ISSN:0960-314X    

出版商:OVID    

年代:1991

数据来源: OVID

ISSN:0960-314X    

出版商:OVID    

年代:1991

数据来源: OVID

ISSN:0960-314X    

出版商:OVID    

年代:1991

数据来源: OVID

ISSN:0960-314X    

出版商:OVID    

年代:1991

数据来源: OVID