Characterisation of CYP3A gene subfamily expression in human gastrointestinal tissues.

McKinnon, Ross A.; Burgess, W M; Hall, P.A.; Robertsthomson, SJ; Gonzalez, F J; McManus, M E

doi:10.1136/gut.36.2.259

Cited by 133 publications

(68 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…However, CYP3A immunoreactivity was consistently identified in type 1 intestinal metaplasia, and immunoreactivity was present in absorptive cells. The most intense CYP3A immunostaining was present in cells closest to the surface, thus mirroring the distribution and cellular localization seen in normal small intestinal epithelium, which shows a gradient of CYP3A immunoreactivity from crypt to villus tip (Murray et al, 1988;McKinnon et al, 1995), with maximum immunoreactivity present in mature absorptive cells at the tip of the villi. This finding suggests that the expression of P450 in metaplastic intestinal epithelium is an intrinsic phenotypic property of those cells that is not influenced by the acid environment of the stomach.…”

Section: Discussionsupporting

confidence: 53%

Enhanced expression of cytochrome P450 in stomach cancer

Murray

Taylor²,

Burke³

et al. 1998

Br J Cancer

View full text Add to dashboard Cite

Summary The cytochromes P450 have a central role in the oxidative activation and detoxification of a wide range of xenobiotics, including many carcinogens and several anti-cancer drugs. Thus the cytochrome P450 enzyme system has important roles in both tumour development and influencing the response of tumours to chemotherapy. Stomach cancer is one of the commonest tumours of the alimentary tract and environmental factors, including dietary factors, have been implicated in the development of this tumour. This type of tumour has a poor prognosis and responds poorly to current therapies. In this study, the presence and cellular localization of several major forms of P450, CYPl A, CYP2E1 and CYP3A have been investigated in stomach cancer and compared with their expression in normal stomach. There was enhanced expression of CYP1 A and CYP3A in stomach cancer with CYP1 A present in 51% and CYP3A present in 28% of cases. In contrast, no P450 was identified in normal stomach. The presence of CYPlA and CYP3A in stomach cancer provides further evidence for the enhanced expression of specific forms of cytochrome P450 in tumours and may be important therapeutically for the development of anticancer drugs that are activated by these forms of P450.Keywords: cytochrome P450; neoplasm; stomach Stomach cancer is one of the commonest cancers of the alimentary tract and has a relatively poor prognosis with limited response to current modes of therapy (Thompson et al, 1993). Environmental factors, particularly dietary factors, are considered to be important in the aetiology and pathogenesis of this type of tumour. The current model for development of stomach cancer proposes that this type of tumour develops from normal stomach through different types of intestinal metaplasia (Correa, 1988).The cytochromes P450 (P450) are a multi-gene family (Nelson et al, 1996) of constitutive and inducible haem-containing enzymes with a critical role in the metabolism of a diverse range of xenobiotics, including many potential carcinogens (Shimada and Guengerich, 1991;Gonzalez and Gelboin, 1994; RobertsThomson et al, 1995) and various anti-cancer drugs (Kivisto et al, 1995a). Thus, the P450s are considered to have a central role in chemical carcinogenesis and are involved in tumour initiation and promotion as they can activate or deactivate most carcinogens (Gonzalez and Gelboin, 1994). Furthermore the P450s can influence the response of established tumours to anti-cancer drugs by metabolizing these drugs both in normal tissues and in tumour cells. In addition, P450s may have a role in cell regulation, in view of their involvement in the metabolism of physiological chemicals active in inter-and intracellular signalling, including steroid hormones, eicosanoids and fatty acids (Capdevila et al, 1992).The liver is the major normal tissue that expresses P450, while specific forms of P450 are expressed in several different normal extra-hepatic tissues, including small intestine, kidney and lung (Schwartzman et al, 1990;Kaminsky and Fasco, 1992; Shima...

show abstract

Section: Discussionsupporting

confidence: 53%

Enhanced expression of cytochrome P450 in stomach cancer

Murray

Taylor²,

Burke³

et al. 1998

Br J Cancer

View full text Add to dashboard Cite

show abstract

“…CYP3A4 is the major form of P450 present in adult human liver, whereas CYP3A5 is only found in approximately 20-25% of livers (Schuetz et al, 1994). However, CYP3A5 appears to be more commonly present in extrahepatic tissues and has been identified in several normal tissues including colon (McKinnon et al, 1995), lung (Anttila et al, 1997), polymorphonuclear leucocytes (Janardan et al, 1996) and anterior pituitary gland while CYP3A7 is the main form of P450 found in human fetal liver (Kitada and Kamataki, 1994). CYP3A can metabolize a variety of carcinogens (Gonzalez and Gelboin, 1994) and several anticancer drugs in clinical use, including ifosphamide (Chang et al, 1993;Walker et al, 1994) and paclitaxel (Harris et al, 1994).…”

Section: Discussionmentioning

confidence: 99%

Cytochrome P450 CYP3A in human renal cell cancer

et al. 1999

View full text Add to dashboard Cite

Renal cell cancer is the commonest malignant tumour of the adult kidney accounting for about 85% of malignant kidney tumours and the incidence of this tumour is steadily rising (Stadler and Vogelzang, 1993;Motzer et al, 1996). The aetiology and pathogenesis of renal cell cancer is not fully understood, although several environmental risk factors have been proposed, including smoking, occupational exposure to heavy metals (e.g. cadmium and arsenic) and obesity. The majority of renal cell cancers are considered to develop from proximal tubular epithelium. Renal cell cancer also responds poorly to wide variety of anti-cancer drugs including vinca alkaloids, etoposide, anthracyclines, taxanes and mitomycin-C (Chapman and Goldstein, 1995;Motzer et al, 1996). Furthermore, agents such as cyclosporin which reverse Pglycoprotein-associated multidrug resistance have not been shown to enhance anti-tumour activity in renal cell cancer (Yagoda et al, 1995).The cytochromes P450 (P450s) are a very large gene family of constitutive and inducible haem containing enzymes. The P450s are classified into families, sub-families and individual forms according to gene sequence homology (individual P450s are identified by the prefix CYP and current P450 nomenclature is outlined in Nelson et al, 1996). There are two broad groups of mammalian P450s. A large group of P450s whose primary role is the oxidative activation and/or deactivation of a wide variety of xenobiotics (CYP1, CYP2, CYP3) while there is a much smaller group of P450s which are constitutively expressed in endocrine glands (adrenal gland, ovary testis) where they are specifically involved in steroid hormone synthesis. Those P450s that have been primarily characterized according to their ability to metabolize xenobiotics are also capable of metabolizing endogenous compounds especially eicosanoids (Capdevila et al, 1992) and steroid hormones (Sarabia et al, 1997) and thus those P450s may also have endogenous functions particularly involvement in cell regulation and cell signalling (Nebert, 1994).The P450s are considered to have a central role in chemical carcinogenesis and are involved in tumour initiation and promotion as they can activate or deactivate many carcinogens (Kawajiri and Fujii-Kuriyama, 1991;Guengerich 1992;Gonzalez and Gelboin, 1994). Furthermore, the P450s can influence the response of established tumours to anti-cancer drugs as P450s are involved in the metabolism of several anti-cancer drugs (Kivistö et al, 1995a).The CYP3A P450 family is one of the main P450 families involved in xenobiotic metabolism including the metabolism of various carcinogens (Gonzalez and Gelboin, 1994; RobertsThomson et al, 1995) and several current anti-cancer drugs (Kivistö et al, 1995a). This family of P450s consists of three closely related forms: CYP3A4, CYP3A5 and CYP3A7. CYP3A4 is the major form of P450 which is constitutively expressed in liver whereas CYP3A5 is only found in a minority of liver samples. However, CYP3A5 appears to show a more widespread constitutive expressio...

show abstract

“…The answer most likely lies in economics rather than technological capability. 33 For example, an interesting development would be technologies that genotype many polymorphic sites (even the whole genome). This would only need to be done once, then the data could be reused as required.…”

Section: Resultsmentioning

confidence: 99%

“…CYP3A4 is also the predominant CYP in human liver where it comprises up to 60% of total CYP content and is also the major CYP in the human intestine. 32,33 Although no evidence exists for a bimodal distribution of CYP3A4 activity, the repeated observation of wide interindividual variability in CYP3A4 activity has prompted close scrutiny of the CYP3A4 gene. To date, more than 20 alleles have been described, several of which result in reduced enzyme activity.…”

Section: Cyp3a4mentioning

confidence: 99%

Cytochrome P450 Part 2: Genetics of Inter‐Individual Variability

Ward¹,

Sorich²,

McKinnon

2008

Pharmacy Practice and Res

View full text Add to dashboard Cite

Inter-individual variability in drug metabolism results from the influence of a myriad of factors, such as concomitant drug therapy and genetic factors. Advances in recombinant DNA technology have enhanced our understanding of the extent of genetic variation in the cytochrome P450 (CYP) enzyme super family, thus clarifying the molecular basis of many clinically observed variations in drug response. This second article in the CYP series describes current understanding of genetic variability in the major drug metabolising CYP enzymes, nomenclature used to describe variant CYP genes, and the clinical significance of such variability. J Pharm Pract Res 2008; 38: 226-9.

show abstract

Characterisation of CYP3A gene subfamily expression in human gastrointestinal tissues.

Abstract: The human CYP3A subfamily is of interest due to its multiplicity, activity toward known carcinogens, and extrahepatic expression. These results show that there is considerable heterogeneity in the expression of the CYP3A subfamily in human gastrointestinal tissues. (Gut 1995; 36: 259-267)

Cited by 133 publications

References 36 publications

Enhanced expression of cytochrome P450 in stomach cancer

Enhanced expression of cytochrome P450 in stomach cancer

Cytochrome P450 CYP3A in human renal cell cancer

Cytochrome P450 Part 2: Genetics of Inter‐Individual Variability

Contact Info

Product

Resources

About