J. Biochem, 1991, Vol. 110, No. 3 407-411
© 1991 Japanese Biochemical Society
research-article |
Genetic Linkage of Lung Cancer-Associated MspI Polymorphisms with Amino Acid Replacement in the Heme Binding Region of the Human Cytochrome P450IA1 Gene1
*Department of Biochemistry, Saitama Cancer Center Research Institute Ina-machi, Kitaadachi-gun, Saitama 362
**Department of Epidemiology, Saitama Cancer Center Research Institute Ina-machi, Kitaadachi-gun, Saitama 362
Individuals with high genetic risk of lung cancer had previously been identified by MspI polymorphisms of the cytochrome P460IA1 gene. In the present study we analyzed the structures of individual P450IA1 genes by PCR direct sequencing of genomic DNA of each genotype raised by the MspI polymorphisms, which were ascribed to a single point mutation in the 3'-flanking region. We then found a novel point mutation in the coding region of the gene which results in the substitution of Ile for Val at residue 462 in the heme binding region. We further analyzed the genetic association between this amino acid replacement and MspI polymorphisms in the general population, using a new method to detect polymorphisms not recognized by restriction enzymes. The results showed that there are at least two forms of human P450IA1 protein with different primary structures and that one of the forms is closely linked with the lung cancer-susceptible genotype ofMspI polymorphisms. Thus MspI polymorphisms, which are associated with increased risk of lung cancer, are linked to at least one amino acid substitution, which gives an important clue, at the molecular level, toward elucidation of increased susceptibility to lung cancer.
1 This work was supported in part by Grants-in-Aid for Scientific Research from the Ministry of Education, Science and Culture of Japan, and a research grant from the Ministry of Health and Welfare of Japan.
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