Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0345904 (liver cancer)
 15,188 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Liver tissues were obtained from 20 liver cancer patients from Thailand, an area where the incidence of this tumour is high and where exposure to aflatoxin occurs. The expression of hepatic cytochrome P450s (P450) and glutathione S-transferase (GST) was examined and this expression was compared to the in vitro metabolism of aflatoxin B1 (AFB1). There was a > 10-fold inter-individual variation in expression of the various P450s including CYP3A4 (57-fold), CYP2B6 (56-fold) and CYP2A6 (120-fold). Microsomal metabolism of AFB1 to AFB1 8,9-epoxide (as measured by AFB1 tris-diol formation) and aflatoxin Q1 (AFQ1), the major metabolite produced, was significantly correlated with CYP3A3/4 expression (P < 0.001) and, to a lesser extent, with CYP2B6 expression (P < 0.01). There was a significantly reduced expression of major P450 proteins in microsomes from liver tumours compared to microsomes from the paired normal liver when analysed by Western immunoblot analysis. The production of AFQ1 and AFB1 tris-diol was almost uniformly reduced in tumours, but interestingly, the production of AFP1 was significantly increased. The immunoreactive expression of the major human classes of cytosolic GSTs (alpha, mu and pi) was also analyzed in normal and tumorous liver tissue. The expression of GSTA (alpha) and GSTM (mu) class proteins was markedly decreased and GSTP (pi) increased in the majority of tumour cytosols compared to normal liver. The cytosolic GST activity (1-chloro-2,4-dinitrobenzene conjugation) was significantly lower in liver tumours compared to normal liver (193 +/- 149 versus 875 +/- 299 nmol/min/mg, P < 0.0001), as was glutathione peroxidase (GPx) activity (cumene hydroperoxide) (26 +/- 23 versus 70 +/- 26 nmol/min/mg respectively, P < 0.005). Ten out of 14 individuals (71%) were homozygous null when genotyped for GSTM1. There was no detectable conjugation of AFB1 8,9-epoxide to glutathione by cytosol either from tumorous or normal liver. Thus, capacity of human cytosols to conjugate reactive AFB1 metabolites to GSH resembled AFB1-sensitive species such as rat, trout and duck rather than resistant species such as mouse and hamster. These data indicate a strong capacity of multiple forms of human hepatic P450s to metabolize AFB1 to both the reactive intermediate AFB1 8,9-epoxide and the detoxification product AFQ1. These results suggest that in view of the lack of significant GST-mediated protection against AFB1 in human liver, variations in expression of hepatic P450, due either to genetic polymorphisms or to modulation by environmental factors, may be important determinants in the risk of liver cancer development in AFB1-exposed populations.
 ...
PMID:In vitro metabolism of aflatoxin B1 by normal and tumorous liver tissue from Thailand. 826 34

The human CYP2A6 enzyme metabolizes certain drugs and pre-carcinogens and appears to be the most important enzyme for nicotine metabolism. At present, more than 10 different allelic variants are known that cause abolished or decreased enzyme activity. Genetic polymorphism in this gene might be of particular importance for an individual's need for nicotine and for susceptibility to lung and/or liver cancer. We have identified a new CYP2A6 allele (CYP2A6*12) which carries an unequal crossover between the CYP2A6 and CYP2A7 genes in intron 2. This results in a hybrid allele where the 5' regulatory region and exons 1-2 are of CYP2A7 origin and exons 3-9 are of CYP2A6 origin, resulting in 10 amino acid substitutions compared to the CYP2A6(*)1 allele. Phenotyping with the CYP2A6 substrate coumarin indicates that it causes reduced CYP2A6 activity in'vivo. Furthermore, when expressed in mammalian COS-1 cells, the enzyme variant catalyzed 7-hydroxylation of coumarin at a rate approximately 60% of that of the wild-type enzyme. The CYP2A6(*)12 allele was present at an allele frequency of 2.2% among Spaniards, but was absent in Chinese.
 ...
PMID:Characterization of a novel CYP2A7/CYP2A6 hybrid allele (CYP2A6*12) that causes reduced CYP2A6 activity. 1232 23

Human cytochrome P450 (CYP) enzymes play a key role in the metabolism of drugs and environmental chemicals. Several CYP enzymes metabolically activate procarcinogens to genotoxic intermediates. Phenotyping analyses revealed an association between CYP enzyme activity and the risk to develop several forms of cancer. Research carried out in the last decade demonstrated that several CYP enzymes are polymorphic due to single nucleotide polymorphisms, gene duplications and deletions. As genotyping procedures became available for most human CYP, an impressive number of association studies on CYP polymorphisms and cancer risk were conducted. Here we review the findings obtained in these studies regarding CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP3A4, CYP3A5, CYP3A7, CYP8A1 and CYP21 gene polymorphisms. Consistent evidences for association between CYP polymorphisms and lung, head and neck, and liver cancer were reported. Controversial findings suggest that colorectal and prostate cancers may be associated to CYP polymorphisms, whereas no evidences for a relevant association with breast or bladder cancers were reported. We summarize the available information related to the association of CYP polymorphisms with leukaemia, lymphomas and diverse types of cancer that were investigated only for some CYP genes, including brain, esophagus, stomach, pancreas, pituitary, cervical epithelium, melanoma, ovarian, kidney, anal and vulvar cancers. This review discusses on causes of heterogeneity in the proposed associations, controversial findings on cancer risk, and identifies topics that require further investigation. In addition, some recommendations on study design, in order to obtain more conclusive findings in further studies, are provided.
 ...
PMID:Cytochrome P450 gene polymorphism and cancer. 1518 Apr 91

A study was conducted to determine the cytochrome (CYP) P450 enzymes responsible for the bioactivation of aflatoxin B1 (AFB1) into its epoxide form (AFBO) in duck liver microsomes. Six male and six female 6-week-old Pekin ducks were used. The biochemical toxicology strategies applied included the use of selective inhibitors, prototype substrate activity for specific human P450s, correlation between aflatoxin bioactivation and enzymatic activity of prototype substrates, and the expression of specific CYP450 enzymes using antibodies against human CYP450s. Enzymatic activity was detected for the duck orthologues CYP1A1/2, CYP2A6 and CYP3A4 but not for the CYP2D6 orthologue. Immunoreactive proteins for CYP1A1, CYP2A6 and CYP3A4 were also detected. Inhibition studies suggested that the duck turkey CYP2A6 orthologue and, to a lesser extent, the CYP1A1 orthologue are involved in the bioactivation of AFB1. Correlation studies, however, suggest that CYP3A4, CYP2A6 and CYP1A1/2 are all involved in AFBO formation. The finding that four CYP enzymes may be involved in AFB1 bioactivation in ducks could explain the high sensitivity of this species to AFB1. Further studies are needed to fully elucidate the phase I hepatic metabolism of AFB1 in ducks, the only poultry species that develops hepatic cancer from AFB1 exposure.
 ...
PMID:The role of selected cytochrome P450 enzymes on the bioactivation of aflatoxin B1 by duck liver microsomes. 2070 84