Human cytochromes P450: evolution and cDNA-directed expression.

As the first step in the process of carcinogenesis, most chemical carcinogens require metabolic activation by cytochromes P450 for conversion to highly reactive electrophiles that bind covalently to DNA. Studies in rodents suggest that low or high levels of expression of a single P450 can determine susceptibility or resistance to chemically induced cancer. Although rodent systems have been used to explore the molecular basis of chemical carcinogenesis and to identify chemicals capable of damaging genes and causing cancer, it has been understood that marked species differences exist in the expression, regulation, and catalytic activities of different P450s. Thus, large efforts are underway to study the catalytic activities of human P450s directly by expression of their cDNAs in cultured cells. Two systems are being used: a) transient high-level P450 production in HepG2 cells for analysis of catalytic activities, and b) stable expression in human B-lymphoblastoid cells to study promutagen and procarcinogen activation. These studies define the relative contributions of individual P450 forms to the activation of various chemical carcinogens. The B-lymphoblastoid cDNA expression system can also be used to determine whether a chemical will be hazardous or toxic to humans. The most intriguing aspects of P450s are the occurrence of human genetic polymorphisms in P450 expression, which could be a risk factor for chemical carcinogenesis. The best-studied P450 genetic polymorphism is the debrisoquine/sparteine polymorphism which is due to mutant CYP2D6 alleles. Four mutant alleles have been characterized that account for most of the defective CYP2D6 genes in Caucasians. These can be detected by polymerase chain reaction assays.(ABSTRACT TRUNCATED AT 250 WORDS)

[1]  M. J. Coon,et al.  Oxygen activation by cytochrome P-450. , 1980, Annual review of biochemistry.

[2]  T. Sugimura,et al.  Carcinogenicity of mutagenic heterocyclic amines formed during the cooking process. , 1985, Mutation research.

[3]  P. Watkins,et al.  Identification of a human liver cytochrome P-450 homologous to the major isosafrole-inducible cytochrome P-450 in the rat. , 1986, Molecular pharmacology.

[4]  D. Nelson,et al.  Evolution of cytochrome P-450 proteins. , 1987, Molecular biology and evolution.

[5]  F. Guengerich,et al.  Metabolism of N-nitrosodialkylamines by human liver microsomes. , 1988, Cancer research.

[6]  O. Mcbride,et al.  Human ethanol-inducible P450IIE1: complete gene sequence, promoter characterization, chromosome mapping, and cDNA-directed expression. , 1988, Biochemistry.

[7]  F. Gonzalez,et al.  The molecular biology of cytochrome P450s. , 1988, Pharmacological reviews.

[8]  T. Aoyama,et al.  cDNA cloning and sequence and cDNA-directed expression of human P450 IIB1: identification of a normal and two variant cDNAs derived from the CYP2B locus on chromosome 19 and differential expression of the IIB mRNAs in human liver. , 1989, Biochemistry.

[9]  O. Mcbride,et al.  Identification of a new P450 expressed in human lung: complete cDNA sequence, cDNA-directed expression, and chromosome mapping. , 1989, Biochemistry.

[10]  P. Srivastava,et al.  Expression of a human liver cytochrome P-450 protein with tolbutamide hydroxylase activity in Saccharomyces cerevisiae. , 1989, Biochemistry.

[11]  U. Thorgeirsson,et al.  Induction of hepatocellular carcinoma in nonhuman primates by the food mutagen 2-amino-3-methylimidazo[4,5-f]quinoline. , 1994, Environmental health perspectives.

[12]  F. Gonzalez,et al.  Human cDNA‐Expressed Cytochrome P450 IA2: Mutagen Activation and Substrate Specificity , 1989, Molecular carcinogenesis.

[13]  T. Aoyama,et al.  Cytochrome P-450 hPCN3, a novel cytochrome P-450 IIIA gene product that is differentially expressed in adult human liver. cDNA and deduced amino acid sequence and distinct specificities of cDNA-expressed hPCN1 and hPCN3 for the metabolism of steroid hormones and cyclosporine. , 1989, The Journal of biological chemistry.

[14]  M. Sari,et al.  Catalytic activities of human liver cytochrome P-450 IIIA4 expressed in Saccharomyces cerevisiae. , 1990, Biochemistry.

[15]  D. Nebert,et al.  Evolution of the P450 gene superfamily: animal-plant 'warfare', molecular drive and human genetic differences in drug oxidation. , 1990, Trends in genetics : TIG.

[16]  F. Gonzalez,et al.  The CYP2A3 gene product catalyzes coumarin 7-hydroxylation in human liver microsomes. , 1990, Biochemistry.

[17]  A. Hinnen,et al.  Constitutive and inducible expression of human cytochrome P450IA1 in yeast Saccharomyces cerevisiae: an alternative enzyme source for in vitro studies. , 1990, Biochemical and biophysical research communications.

[18]  M. P. Arlotto,et al.  Human cytochrome P450IIA3: cDNA sequence, role of the enzyme in the metabolic activation of promutagens, comparison to nitrosamine activation by human cytochrome P450IIE1. , 1990, Carcinogenesis.

[19]  T. Aoyama,et al.  Five of 12 forms of vaccinia virus-expressed human hepatic cytochrome P450 metabolically activate aflatoxin B1. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[20]  M. Relling,et al.  Tolbutamide and mephenytoin hydroxylation by human cytochrome P450s in the CYP2C subfamily. , 1990, The Journal of pharmacology and experimental therapeutics.

[21]  T. Aoyama,et al.  Identification of a new variant CYP2D6 allele lacking the codon encoding Lys-281: possible association with the poor metabolizer phenotype. , 1991, Pharmacogenetics.

[22]  F. Gonzalez,et al.  The development of a human cell line stably expressing human CYP3A4: role in the metabolic activation of aflatoxin B1 and comparison to CYP1A2 and CYP2A3. , 1991, Carcinogenesis.

[23]  U. Meyer,et al.  Polymerase chain reaction-directed identification, cloning, and quantification of human CYP2C18 mRNA. , 1991, Molecular pharmacology.

[24]  D W Nebert,et al.  The P450 superfamily: update on new sequences, gene mapping, and recommended nomenclature. , 1991, DNA and cell biology.

[25]  P. Vineis,et al.  Relevance of metabolic polymorphisms to human carcinogenesis: evaluation of epidemiologic evidence. , 1991, Pharmacogenetics.

[26]  T. Shimada,et al.  Oxidation of toxic and carcinogenic chemicals by human cytochrome P-450 enzymes. , 1991, Chemical research in toxicology.

[27]  M. Romkes,et al.  Cloning and expression of complementary DNAs for multiple members of the human cytochrome P450IIC subfamily. , 1991, Biochemistry.