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United States Patent (19) 11 Patent Number: 4,791,057 Misaki Et Al

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United States Patent (19) 11 Patent Number: 4,791,057 Misaki Et Al United States Patent (19) 11 Patent Number: 4,791,057 Misaki et al. (45) Date of Patent: Dec. 13, 1988 (54) HIGHLY SENSITIVE ENZYMATIC ASSAY 57 ABSTRACT METHOD A highly sensitive quantitative assay method for a com 75 Inventors: Hideo Misaki; Shigeru Ueda, both of ponent which is 3,3-hydroxysteroid or 3-ketosteroid, in Shizuoka, Japan a specimen to be assayed, comprising causing this com ponent in the specimen to take part in the cycling reac 73) Assignee: Toyo Jozo Kabushiki Kaisha, Shizuoka, Japan tion (21) Appl. No.: 757,953 36-hydroxysteroid oxidase 22 Filed: Jul. 23, 1985 (30) Foreign Application Priority Data O2 H2O2 Jul. 23, 1984 (JP) Japan ................................ 59-151438 3,3-hydroxy 3-ketosteroid 51 Int. Cl." ......................... C12Q 1/26; C12O 1/32; steroid C12Q 1/28 NAD(P) reduced NAD(P) 52 U.S. Cl. ........................................ 435/26; 435/25; 435/28; 436/817 3,3-hydroxysteroid 58) Field of Search ..................... 435/25, 26, 28, 192; dehydrogenase 436/817 and measuring a detectable change in the reaction sys (56) References Cited tem. There is thus provided a 36-hydroxysteroid - 3 U.S. PATENT DOCUMENTS ketosteroid cycling reaction using 3,3-hydroxysteroid oxidase, which consumes O2 and generates H2O2 and 4,230,797 10/1980 Boguslaski et al...................... 435/7 3-ketosteroid, with a substrate of 36-hydroxysteroid, or OTHER PUBLICATIONS 3,3-hydroxysteroid dehydrogenase, which consumes reduced NAD(P) and generate NAD(P) and 36 Hurlock et al. (1956) Society of Experimental Biology hydroxysteroid, with a substrate of 3-ketosteroid. Ex and Medicine Proceedings, vol. 93, pp. 560-564. ample of specimens are specimens which contain 3 Yamagouchi et al. (1981) Analytical Letters, vol. 14, hydroxysteroid or 3-ketosteroid, or which liberate or No. B6, pp. 433-438. generate such a component. By proceeding at a rate of Dolin, 1957 Science, vol. 225, pp. 557-573. more than ten cycles per minute and measuring the Blaedel et al. (1978), Analytical Chemistry, vol. 50, No. amount of a detectable change in the reaction, the com 8, pp. 1026-1032. ponent in a specimen can easily and sensitively be de Primary Examiner-Robert J. Warden tected with good accuracy. Assistant Examiner-Jack Spiegel Attorney, Agent, or Firm-Young & Thompson 8 Claims, 3 Drawing Sheets U.S. Patent Dec. 13, 1988 Sheet 1 of 3 4,791,057 CN g CN ar s g to s N (\ - O O O O O O NW O/WN Ot/9 LW S39)NWHO NOLc OS 9W U.S. Patent Dec. 13, 1988 Sheet 2 of 3 4,791,057 2 > O 1 2 V - 2. O C CD to O O O O O o O OO CO Q CN (%) NO WISNOO N39)XO O an NO Ll NO O 3 t O - R3 CD d o to li- S. 13L O O S - : o a Q S o CS O O O O NW O/WN Ot?9 LW SGS)NWHO NOLOS 9W U.S. Patent Dec. 13, 1988 Sheet 3 of 3 4,791,057 2 2 CO Os He O N orH , CD 2 CU 2.L () (O l O O O2Z - O 5 CD Z, 3. O (?) to (i. m O O O S d NW O / WN Ot/9 LW S39)NWHO NOLOS 9W 4,791,057 1. 2 by heating under alkaline conditions, and the said alkali HIGHLY SENSTIVE ENZYMATIC ASSAY then be neutralized, are required. METHOD The concentration of steroid hormones in vital speci mens is generally low and so direct assay by spectro This invention relates to a quantitative assay method 5 photometry has been difficult. In the prior art of assay for a component in a specimen to be assayed, which methods, hydroxysteroid is treated with 3-hydroxys component can be 3,3-hydroxysteroid or 3-ketosteroid. teroid dehydrogenase and NAD to generate reduced More particularly the present invention relates to a NAD which is colorimetrically measured at 350 mm. highly sensitive enzymatic assay method which com But this method is of low sensitivity and hence trace prises reacting a component in the specimen with the 10 steroid horomones in serum, except cholesterol, cannot components of the cycling reaction be measured. We have now discovered a 3.3-hydroxysteroid-3- 3,3-hydroxysteroid I ketosteroid cycling reaction using 3.3-hydroxysteroid oxidase oxidase, which consumes O2 and generates H2O2 and O2 H2O2 15 3-ketosteroid, with a substrate of 3,3-hydroxysteroid, and furthermore 3,6-hydroxysteroid dehydrogenase, 3.3-hydroxy- 3-ketosteroid which consumes reduced NAD(P) and generates steroid NAD(P) and 36-hydroxysteroid, with a substrate of NAD(P) reduced NAD(P) 3-ketosteroid. 3,3-hydroxysteroid 20 These reagents can be obtained at low cost and good dehydrogenase quality, and moreover an effective cycling reaction can and measuring the amount of detectable change in the be achieved in spite of coexisting oxidatively active reaction system. H2O2 and reductively active reduced NAD. Further Enzymatic cycling assay methods such as NAD cy- 25 more, we have found that in the cycling reaction, 343 cling, NADP cycling or CoA cycling are known. For hydroxysteroid or 3-ketosteroid in a specimen is reacted example, alcohol dehydrogenase has been subjected to with the remainder of the other components in the cy reaction with ethanol as a substrate in the presence of cling reaction system consisting of 3,3-hydroxysteroid, NAD to form reduced NAD which is oxidized to NAD 3-ketosteroid, 36-hydroxysteroid oxidase, 3,3-hydrox by the action of malic dehydrogenase on a substrate of 30 ysteroid dehydrogenase, NAD(P), reduced NAD(P), oxalacetate to constitute an NAD-reduced NAD cy O2 or H2O2, and that, by proceeding at a rate of more cling reaction. Jap. Biochem. Soc. Ed. "Experimental than ten cycles per minute and measuring the amount of Methods in Biochemistry”, Vol. 5, "Research Methods in a detectable change in the reaction, the target compo Enzymology', p. 121-135, Tokyo Kagaku Dojin Pub nent in a specimen can easily and sensitively be detected lishing Co., August 1975, Mori, A. Ed. "Manual of 35 with good accuracy. Assay Methods in Neuro-transmittance', p. 165-172, An object of the present invention is to provide a Ishiyaku Publishing Co., November 1979. simple and highly sensitive enzymatic assay method, Another method is known as follows: without necessitating complicated pre-treatment as in In the above reaction, malic dehydrogenase is re known assay methods for 33-hydroxysteroid or 3-ketos placed by reduced NAD oxidase to constitute a cycling teroid in a specimen, by the use of a coenzyme cycling reaction wherein oxygen and reduced NAD are con reaction. sumed and H2O and NAD are generated Institute for These objects are achieved, according to the present Phys. and Chem. Sci. Ed.: “Present and Future of Life invention, by the method which we have discovered, Science', p. 30-32, K. K. Creative Life Sci. Res. Assn., which comprises reacting a component in the specimen March 1981). Hydroxysteroid is treated with hydroxys 45 with the components of the cycling reaction teroid dehydrogenase to reduce NAD to reduced NAD which is converted to NAD with the formation of for 3p3-hydroxysteroid I mazane by the action of a transferase such as diaphorase oxidase in the presence of a tetrazolium salt to constitute the O2 H2O2 cycling reaction Jap. Pat. Unexam. Publ. No. 50 56-144096). Glutathione and dehydroascorbate are treated with 3p3-hydroxy- 3-ketosteroid glutathione dehydroascorbate oxido-reductase, thereby steroid converting dehydroascorbate to ascorbate, which con NAD(P) reduced NAD(P) sumes oxygen and generates H2O and dehydroascor- 55 3,3-hydroxysteroid bate by the action of ascorbate oxidase to constitute a dehydrogenase cycling reaction. Jap. Pat. Unexam. Publ. No. 56-151498. NAD cycling wherein oxygen is consumed and measuring the amount of a detectable change in the and hydrogen peroxide is generated by using reduced reaction system. NAD oxidase is also known Jap. Pat. Unexam. Publ. Examples of specimens are specimens which contain No. 56-78599). 3,3-hydroxysteroid or 3-ketosteroid, or which liberate As mentioned hereinabove, several kinds of cycling or generate such a component. In the latter case, meta reaction systems have been reported, however, the one bolic systems and biosynthetic systems of various ste most frequently used, in which reduced NAD oxidase roid hormones, which are classified into, for example, generates peroxide, suffers from the difficulty of purifi- 65 androgens in male animals, estrogen or gestagen in cation, so that an accurate assay cannot be expected. female animals, and corticoid in both sexes, can be men Furthermore, in NAD cycling methods, complicated tioned. An enzymatic activity which characterizes these processes wherein excess NAD has to be decomposed systems, or the amount of 3,3-hydroxysteroid or 3 4,791,057 3 4. ketosteroid, can be determined. Examples thereof are as follows: 3,3-hydroxysteroid I 3,3-hydroxysteroid: oxidase (1) Androgen: O2 H2O2 pregnenolone, 17a-hydroxypregnenolone, dehydro- 5 epiandrosterone, androstene-3,3,1713-diol, androstane 3,3-hydroxy 3-ketosteroid 36,176-diol, A-androsterone-3p3,17a-diol, androstane steroid 3,3,116-diol-17-one. (2) Estrogen: ,36-hydroxysteroid reduced NAD(P) estradiol, estrone, estriol, equilin, equilenin, 10 dehydrogenase ethynylestradiol. 3-ketosteroid: In the reaction I), one mole of 3,3-hydroxysteroid is (1) Androgen: converted with the consumption of one mole of O2, progestreone, 17a-hydroxyprogesterone, testoster generally dissolved oxygen, to one mole of 3-ketos one, androstenedione. 15 teroid with the generation of one mole of H2O2 by the (2) Corticoid: action of 3,3-hydroxysteroid oxidase to constitute the corticosterone, cortisol, cortisone. 3p3-hydroxysteroid oxidase reaction system.
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