Expression and localization of CYP3A4 and CYP3A5 in human lung.

Anttila, Sisko; Hukkanen, Janne; Hakkola, Jukka; Stjernvall, Tuula; Beaune, Philippe; Edwards, Robert J.; Boobis, Alan R.; Pelkonen, Olavi; Raunio, Hannu

doi:10.1165/ajrcmb.16.3.9070608

Cited by 143 publications

(103 citation statements)

References 27 publications

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“…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

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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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Section: Discussionmentioning

confidence: 99%

Cytochrome P450 CYP3A in human renal cell cancer

et al. 1999

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“…One microgram of total RNA from gallbladder-derived BEC and from human liver, Caco-2, or HepG2 cells was submitted to CYP3A4, CYP3A5, and CYP3A7 reverse-transcription polymerase chain reaction (RT-PCR) as described. 6 The primers were previously designed to localize in separate exons and in the least homologous cDNA sequences. 6 After 35 cycles, the PCR products were hybridized with internal ␥-32 P-ATP-labeled oligonucleotide probes that were chosen according to published cDNA sequences, using the oligo4 program (National Sciences): 5Ј GTT GAG TCA AGG GAT GGC ACC GTA AGT GGA 3Ј, 5Ј GTA CTG GAC AGA GCC TGA GGA GTT CCG CCC 3Ј, and 5Ј TTC CAA GCT ATG TTC TTC ATC ATG ACC CAA 3Ј corresponding to nucleotides 1545-1574 of CYP3A4, 1312-1341 of CYP3A5, and 1187-1216 of CYP3A7 cDNAs, respectively.…”

Section: Methodsmentioning

confidence: 99%

“…The resulting metabolites are often electrophilic compounds that can bind to cellular proteins or nucleic acids and alter cell functions. Although CYP enzymes and their associated mono-oxygenase activities are most abundant in hepatocytes, 1,2 a number of isoforms have been identified in most extrahepatic tissues including the intestine 1,2,6 as well as in nonparenchymal liver cells. 1,7,8 The reactive electrophilic intermediates produced by CYP enzymes may be detoxicated by microsomal epoxide hydrolase (mEH) into dihydrodiols, which are easy to eliminate.…”

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confidence: 99%

Phase I and Phase II drug-metabolizing enzymes are expressed and heterogeneously distributed in the biliary epithelium

et al. 1999

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Tissue expression of drug-metabolizing enzymes influences susceptibility to drugs and carcinogens. Because the biliary epithelium, exposed to bile-borne chemicals, may give rise to drug-induced cholangiopathies and to cholangiocarcinomas, we determined the pattern of expression of drug-metabolizing enzymes in this epithelium. We first demonstrated by blot analyses that biliary epithelial cells (BEC) isolated from human gallbladders display cytochrome P450 (CYP) 1A, 2E1, and 3A, microsomal epoxide hydrolase (mEH), ␣, , and glutathione S-transferase (GST), transcripts and proteins. We also identified CYPassociated steroid 6␤-hydroxylase activity in BEC. CYP and mEH expression was 5-to 20-fold lower in BEC than in autologous hepatocytes, and further differed by a higher ratio of CYP3A5/CYP3A4, and by CYP1A1 predominance over CYP1A2. ␣GST was highly expressed in both hepatocytes and BEC, while GST was restricted to BEC. In approximately 50% of individuals, GST was expressed in hepatocytes and at lower levels in BEC. By using the same antibodies as those used in immunoblots, we could show by immunohistochemistry that CYP2E1, CYP3A, mEH, ␣, , and GST immunoreactivities are expressed and display a heterogeneous distribution in the epithelium lining the entire biliary tract except for small intrahepatic bile ducts that were devoid of CYP3A and ␣GST immunoreactivities. In conclusion, BEC contribute to phase II, and although to a lesser extent than hepatocytes, to phase I biotransformation. The distribution of drug-metabolizing enzymes in BEC suggest that they are heterogeneous in their ability to generate and detoxicate reactive metabolites, which may contribute to specific distributions of cholangiopathies. (HEPATOLOGY 1999;30:1498-1506.)Foreign compounds including procarcinogens and drugs are widely distributed in our environment. The liver is the major organ responsible for their biotransformation into more hydrophilic products, and elimination through bile secretion. Biotransformation results from the activities of phase I and phase II metabolizing enzymes that are mainly, although not exclusively, located within hepatocytes.

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“…Finally, a recent study shows considerable variation in the human pulmonary CYP3A4 and CYP3A5 expression (Anttila et al 1997). …”

Section: Pah Exposure In Humansmentioning

confidence: 99%