A NEW DELETED ALLELE IN THE HUMAN CYTOCHROME-P450 2A6 (CYP2A6) GENE FOUND IN INDIVIDUALS SHOWING POOR METABOLIC CAPACITY TO COUMARIN AND (-CIS-3,5-DIMETHYL-2-(3-PYRIDYL)THIAZOLIDIN-4-ONE HYDROCHLORIDE (SM-12502)())

The S-oxidation of +)-cis-3,5-dimethyl-2-(3-pyridyl)thiazolidin-4-one hydrochloride (SM-12502) and the 7-hydroxylation of coumarin are prima rily catalyzed by cytochrome P450 2A6 (CYP2A6), The activities of SM-1 2502 S-oxidase and coumarin 7-hydroxyrase were investigated with liver microsomes from 20 human individuals, Liver microsomes from individua l H16 showed the lowest activities of both enzymes. The expression of CYP2A6 protein was not detectable in liver microsomes from individuals H4, H5, H7, H8, H12 and H16. CYP2A6 mRNA was hardly detectable in the liver of the individual H16. A new SacI-restriction fragment length p olymorphism showing the lack of a 2.6 kb fragment was found in two of forty genomic DNA preparations from individuals H16 and No, 594, using CYP2A6 cDNA as a probe. This deletional 2.6 kb fragment was isolated from a genomic library prepared from one individual showing normal cou marin 7-hydroxylase activity and was sequenced. This fragment containe d a CYP2A6 gene region from 319 bp upstream of a putative exon 6 to a SacI site in exon 9, indicating that this region was deleted in the tw o individuals in this study, We also demonstrated by polymerase chain reaction analysis that the exon 8 of CYP2A6 gene was deleted in indivi duals H16 and No, 594, These results indicate that the reduced activit y of SM-12502 S-oxidase and no activity of coumarin 7-hydroxylase are caused by the lack. of CYP2A6 mRNA and CYP2A6 protein caused by the CY P2A6 gene deletion. Pharmacogenetics 8:239-249 (C) 1998 Lippincott-Rav en Publishers.