Cytochrome P450 CYP3A in human renal cell cancer

Abstract

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...

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