Cancer Letters

Cancer Letters

Volume 139, Issue 2, 24 May 1999, Pages 199-205
Cancer Letters

Differential expression of CYP1A1, CYP1A2, CYP1B1 in human kidney tumours

https://doi.org/10.1016/S0304-3835(99)00045-2Get rights and content

Abstract

The presence of mRNA of individual members of the CYP1 gene family in normal and neoplastic kidney has been investigated by RTPCR. CYP1B1 mRNA was consistently expressed in both normal and neoplastic kidney while CYP1A1 was present in the majority of normal and neoplastic whereas CYP1A2 was infrequently expressed. Expression of the Ah receptor and Arnt which are involved in the transcriptional activation of the CYP1 genes was also studied. The Ah receptor mRNA and Arnt mRNA were consistently expressed both in kidney tumours and normal kidney. These results indicate differential expression of individual members of the CYP1 gene family in normal and neoplastic kidney and suggest that several mechanisms including the Ah receptor complex could be involved in their regulation.

Introduction

The cytochromes P450 (P450) are a very large gene family of constitutive and inducible enzymes with a major role in the oxidative activation and/or deactivation of a wide range of xenobiotics including many potential carcinogens [1], [2] and several anticancer drugs [3]. The P450s can influence the response of established tumours to anticancer drugs by metabolising these drugs both in normal tissues and tumours [3]. The human CYP1 gene family is one of the major P450 families involved in the metabolism of xenobiotics and consists of three individual forms classified into two distinct subfamilies. The CYP1A subfamily contains two closely related but distinct members, CYP1A1 and CYP1A2, CYP1A1 is an inducible P450 [4] primarily in extrahepatic tissues while CYP1A2 is a major form of P450 that is constitutively expressed in liver [5], [6]. CYP1B1 is the only known member of a new subfamily of CYP1 which was initially isolated from a human keratinocyte cell line and shown to be inducible by dioxin [7]. Recent studies have suggested that CYP1B1 may be a marker of tumourigenesis especially malignant transformation [8].

One of the mechanisms of transcriptional regulation of members of the CYP1 gene family is via the Ah receptor complex [9], [10]. The Ah receptor complex consists of two components, the Ah receptor and Arnt (aryl hydrocarbon nuclear translocator), which are both members of the basic helix-loop-helix family of transcription factors [11]. Binding of ligands, e.g. polycyclic aromatic hydrocarbons and dioxin to the Ah receptor causes ‘transformation’ of the Ah receptor. After transformation, the activated Ah receptor is translocated from the cytoplasm to the nucleus where it forms a heterodimer with Arnt and the complex binds to specific upstream regulatory DNA sequences (xenobiotic or dioxin responsive elements) to activate transcription in responsive genes [9], [10]. Dioxin responsive elements have been identified in the upstream regulatory sequences of the CYP1A1 [12], CYP1A2 [13] and CYP1B1 genes [14]. Studies on the expression of CYP1A1 and CYP1B1 in human tumour derived cell lines suggests that there may be cell type-specific expression of CYP1A1 and CYP1B1 [15], [16] although all the cell lines studied contain Ah receptor.

In this study we have investigated the expression of individual members of the CYP1 gene family in neoplastic kidney and corresponding normal kidney and compared the expression of these forms of P450 with that of both the Ah receptor and Arnt.

Section snippets

Tissue

Paired samples of renal cancer and corresponding normal kidney were obtained from patients (male 21, female 6: age range 39–88) who underwent surgery for primary kidney cancer. The resected specimens of kidney had been submitted to the Department of Pathology, University of Aberdeen, for histopathological diagnosis. All the tumours were primary renal cell cancers and the histological classification of the tumours performed according to current criteria [17] showed 23 clear cell carcinomas, two

Results

β-actin was detected in all the normal and tumour samples (Fig. 1) and all the samples of normal and neoplastic kidney were subject to PCR for the individual P450s, Ah receptor and Arnt. CYP1A1 mRNA was present in 22/27 (81%) of the kidney tumour samples while CYP1A1 mRNA was detected in 22/27 (81%) of normal kidney samples. In three cases neither tumour nor normal kidney samples expressed CYP1A1 while in another two cases CYP1A1 was only present in the tumour samples without expression of

Discussion

In this study we have investigated the expression of CYP1A1 mRNA, CYP1A2 mRNA and CYP1B1 mRNA in normal and neoplastic kidney. The expression of these forms of P450 was compared with the expression of the Ah receptor mRNA and Arnt mRNA. The Ah receptor and Arnt heterodimerise to form the Ah receptor complex which is involved in the transcriptional activation of individual members of the CYP1 gene family especially CYP1A1 and CYP1B1 [9], [10]. There was differential expression of individual

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