REGULATION OF CYTOCHROME-P450 GENE-EXPRESSION IN HUMAN COLON AND BREAST-TUMOR XENOGRAFTS

It is extremely difficult to identify the factors which regulate the e xpression of drug-metabolising enzymes in man. To address this problem , we have developed a model involving the use of human tumours grown a s xenografts in immune deficient mice. Mice bearing human colon or bre ast tumours as xenografts were challenged with a range of compounds, k nown from animal studies to be inducers of cytochrome P450s from a var iety of gene families. Almost all of the compounds tested could induce human tumour P450 expression, measured either by Western blot or immu nohistochemical analysis. Indeed, the levels of P450s from several dis tinct gene families or subfamilies including CYP2A, CYP2B, CYP2C, CYP3 A and CYP4A were induced. Of particular interest was the profound indu ction of human P450s by 1,4 bis 2-(3,5dichloro-pyridyloxybenzene)(TCPO BOP), a compound which exhibits a marked species specificity in its ab ility to induce P450 expression in experimental animals. Induction of a human CYP2B protein by this compound was confirmed by Northern blot analysis and in situ hybridisation for mRNA, indicating that induction occurred at the level of transcription. These studies have a variety of implications: they provide a method for approaching the previously intractable problem of how environmental, hormonal and metabolic facto rs regulate human P450 genes and other genes involved in drug metaboli sm; they demonstrate that human tumours express P450s constitutively a nd that the levels of these proteins can be modulated by exogenous age nts.