Molecular Genetics of the Human Cytochrome P450-Dependent Monooxygenases.

Abstract

In this work, the role of genetic as well as environmental factors in determining cytochrome P450 isozyme levels in man have been studied. Simple DNA based assays for the identification of individuals nulled at the CYP2D6 locus are described and have been applied to investigate whether this gene defect is associated with altered cancer susceptibility. In contrast to literature reports, in no cancer type were poor metabolizers underrepresented, indeed in several cancers the mutant allele frequency was increased. A model using human tumours grown as xenografts is described that should help elucidate the factors which regulate P450 levels in man.human cytochrome P-450; cancer susceptibility ; mutant allele frequency ; CYP2D6 ; human tumor xenograft Cytochrome P450-dependent monooxygenases play a central role in the metabolism of drugs, chemical toxins and carcinogens. Individuality in the expression of P450 genes may therefore play an important role in individual susceptibility to diseases such as cancer. In this report we describe work on the environmental and genetic factors which regulate cytochrome P450 levels in man.The reactions catalyzed by these enzymes usually involves the incorporation of an atom of molecular oxygen into the substrate. In most cases this results in increased hydrophilicity and facilitates excretion. However, in certain cases this metabolic process results in the activation of the prodrug or procarcinogen converting it into its ultimate carcinogenic form. Possibly as a consequence of the central role of this enzyme system in detoxification, the cytochrome P450-dependent monooxygenases have evolved into a series of multigene families and in man there may be fifty or more distinct enzymes active in foreign compound metabolism (Nebert et al. 1991). Each of these forms exhibits its own unique Address for reprints ;

The site of general anaesthesia and cytochrome P450 oxygenases: similarities defined by straight chain and cyclic alcohols

“…In this paper we describe the effects of alcohols on the NADPH‐dependent metabolism of aminopyrine by microsomes prepared from rat liver. Demethylation of aminopyrine appears to be catalysed primarily by P450 isozymes from gene families 2B and 2C (Wolf et al , 1990) and 1B and 1C (Ichihara et al , 1985). Thus, multiple isozymes are apparently operative in the present experiments.…”