Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Patent
1996-11-05
1998-10-13
LeGuyader, John L.
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
435 911, 536 231, 536 2431, 536 2433, C12Q 168, C12P 1934, C07H 2102, C07H 2104
Patent
active
058210628
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to an oligonucleotide for checking the presence or absence of mutation in a human-derived cytochrome P450IIC18 gene which is one of the enzymes participating in the metabolic decomposition of medicines. More particularly, the present invention relates to an oligonucleotide which is used to recognize or amplify a DNA having the base sequence of the gene and which is useful for diagnosing and analyzing the presence or absence of mutation before the administration of a medicine.
BACKGROUND ART
Cytochrome P450 is one of the metabolizing enzymes, in liver, participating in the metabolic decomposition of a variety of medicines. It has many molecular species and about twenty kinds of species are confirmed now in human beings. Among these molecular species, human-derived cytochrome P450IIC18 has been extensively studied on its ability to in vivo metabolize medicines (for example, tricyclic antidepressants such as amitriptyline, imipramine and the like, antiepileptics such as S-mephenytoin, ethotoin and the like, proton pump inhibitors such as omeprazole and the like, benzodiazepine preparations which are minor tranquilizers such as diazepam and the like, .beta.-blocking agents such as propranolol and the like, and sleep inducing barbiturates such as hexobarbital and the like). However, individual differences in actual drug reaction and the like could not be explained. This is due to the presence of genetic polymorphism caused by mutation in human-derived cytochrome P450IIC18 and the relationship between this genetic polymorphism and the individual differences in drug reaction was not understood.
By the way, if the relationship between genetic polymorphism and individual differences in drug reaction is revealed, it becomes possible to easily predict the manifestation of the side effects and the conversion into an active form metabolite. That is, if the cause of genetic polymorphism (for example, mutation in a gene) in the enzymes (the enzyme means human-derived cytochrome P450IIC18 in the present invention) participating in the metabolic decomposition of medicines is revealed, it becomes possible to determine a safe dose of a medicine which has been difficult to use because of the occurrence of individual differences in drug-metabolizing function, by means of diagnosing and analyzing the presence or absence of mutation in such the gene before the administration of a medicine. It also becomes possible to use a medicine which takes an active form by the action of the enzyme according to individuals.
For this reason, there is a problem that, in order to clarify the relationship between genetic polymorphism of the enzymes participating in the metabolic decomposition of medicines and individual differences in drug reaction, when that genetic polymorphism is caused by mutation in a gene of the enzymes, what kind of mutation can be used and how the presence or absence of mutation in the gene can be diagnosed and analyzed before the administration of a medicine.
DISCLOSURE OF THE INVENTION
In view of the above situation, the present inventors studied hard to clarify the relationship between genetic polymorphism of the enzymes participating in the metabolic decomposition of medicines and individual differences in drug reaction. As the result, the present inventors have discovered that the relationship between genetic polymorphism of a specific enzyme and individual differences in drug reaction is based on mutation in the enzyme gene and that the presence or absence of mutation in such a gene can be checked by hybridization analysis of the base sequence including that of the mutated site or by the presence or absence of the action of a restriction enzyme which recognizes the base sequence of the mutated site. And the present inventors found out an oligonucleotide for recognizing or amplifying a DNA having a mutated site in the specific enzyme gene upon above checking, that is, an oligonucleotide for diagnosing and analyzing the presence or absence of mutation in the specif
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Kaneko Hideo
Komai Koichiro
Nakatsuka Iwao
LeGuyader John L.
Sumitomo Chemical Company Limited
Wang Andrew
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