Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Patent
1996-03-06
1998-02-17
Sisson, Bradley L.
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
435 911, 435 912, 536 235, 536 2431, 536 2433, 935 8, 935 14, 935 77, 935 78, C12Q 168, C12P 1934, C07H 2104, C12N 1500
Patent
active
057190267
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to a method for diagnosing genes of drug metabolism-associated enzymes, and more particularly to a method for detecting polymorphism of the human cytochrome P4501A2 gene (hereinafter abbreviated as CYP1A2).
BACKGROUND ART
Human cytochrome P450 has important functions including detoxication and metabolic activation of drugs or exogenous materials and biosynthesis of steroid hormones and bile acid. CYP1A2 is one of the cytochrome P450 molecular species and is known to have a function of metabolizing drugs such as theophylline and phenacetin. The activity of CYP1A2 can be confirmed by a so-called caffeine test in which caffeine metabolites in urine after intake of coffee are quantitatively measured. It is known that the caffeine test has proved that there are poor metabolizers (hereinafter abbreviated as PMs) and extensive metabolizers (hereinafter abbreviated as EMs).
If a certain drug serves as a specific substrate for CYP1A2, it is considered that administration of the drug to PMs causes excessively strong effects (side effects) because PMs maintain high concentrations of the drug in blood. In fact, when theophylline is administered to PMs, about 30% of them are said to show side effects. To prevent side effects of this type which are manifested intensely due to polymorphism in drug metabolic activities, and if it is possible to distinguish extensive metabolizers and poor metabolizers by a gene diagnosis before administering a drug, better medicinal therapy directed to each patient can be achieved.
Similar polymorphism has been observed in other drug metabolizing enzymes such as CYP1A1, CYP2D6, and N-acetyltransferase. It is reported that the polymorphism of the drug metabolizing activity is attributed to gene polymorphism, and therefore, whether the patient is a PM or EM can be easily determined by gene diagnosis. However, with respect to CYP1A2, gene polymorphism has not yet been found.
The present invention clarifies a novel mutation of CYP1A2, and provides a new method for detecting gene polymorphism of CYP1A2.
DISCLOSURE OF THE INVENTION
The present inventors conducted an analysis of CYP1A2 genes of healthy human subjects and found a new polymorphism of the gene. They were also successful in developing a detection method therefor, leading to completion of the present invention.
Accordingly, the present invention provides a method for detecting polymorphism of the CYP1A2 gene characterized in that substitution at a 2064th base (mutation 1) present in a nontranslational region of the CYP1A2 gene is detected.
The present invention also provides a method for detecting polymorphism of the CYP1A2 gene characterized in that substitution at a 2640th base (mutation 2) present in a nontranslational region of the CYP1A2 gene is detected.
The present invention further provides a method for detecting polymorphism of CYP1A2 gene characterized in that deletion of a -1569th base (mutation 3) present in a nontranslational region of the CYP1A2 gene is detected.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 shows the relation among types of gene polymorphism and the half life of theophylline in blood.
In FIG. 1, the ordinate represents the half life of theophylline and the abscissa represents types of gene polymorphism. Graph (A) and graph (B) show the results of detecting the 2640th polymorphism and -1549th polymorphism, respectively. The types of polymorphism shown in FIG. 1 are as follows:
BEST MODE FOR CARRYING OUT THE INVENTION
In the present invention, nucleotide sequences are expressed by symbols in accordance with definitions given by IUPAC-IUB and common names or common usage in the art. The nucleotide numbers of the above-mentioned mutation 1 and mutation 2 are expressed in accordance with CYP1A2 genome DNA (Mol. Endocrinol. 3 (9), 1399-1408 (1989)), and the nucleotide number of mutation 3 is expressed in accordance with CYP1A2 genome DNA (Mol. Pharmacol., 36 (1), 66-71 (1989)). The content of Mol. Endocrinol. 3 (9), 1399-1408 (1989) and Mol. Pharmacol., 36
REFERENCES:
Botsch et al., "Identification and Characterization of the Cytochrome P450 enzymes involved in N-dealkylation of Propafenone: Molecular Base for Interaction Potential and Variable Disposition of Active-Metabolites," Molecular Pharmacology, vol. 43, No. 1, 1993.
Analytical Biochemistry, vol. 222, No. 1 1994 (94), B.B. Rasmussen (Determination of theophylline metabolites in human liver microsomes by high-performance liquid chromatography) pp. 9-13.
Molecular Pharmacology, vol., 43, No. 1 1993 (93), S. Botsch (Identification and characterization of the cytochrome P450 enzymes involved in N-dealkylation of propafenone: Molecular base for interaction potential and variable disposition of active-metabolites) pp. 120-126.
Fukui Takafumi
Katsuragi Kiyonori
Kinoshita Moritoshi
Shin, deceased Sadahito
Otsuka Pharmaceutical Co. Ltd.
Sisson Bradley L.
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