Activation of monooxygenases in human liver by 7,8-benzoflavone Addition of /0-4 M 7,8-benzojlavone to homogenates of human liver samples obtained by autopsy or surgical biopsy increased the rate of benzo [a] pyrene hydroxylation up to II-fold. 7,8-Benzojlavone also increased the rates of hydroxylation of zoxazolamine and antipyrine at /0-4 M but inhibited these reactions at /0-6 M. The effects of 7,8-benzojlavone on the hydroxylation of benzo[a]pyrene and zoxazolamine in microsomes from human liver were similar to those in homogenates. Addition of 7,8-benzojlavone to homogenates of surgical biopsy samples of human liver had little or no effect on the rates of oxidative metabolism of 7-ethoxycoumarin, coumarin, and hexobarbital. Marked individuality for the activating and inhibiting effects of 7,8-benzojlavone was observed in different liver samples. This individuality may result both from the presence of multiple monooxygenases in varying amounts and proportions in the different liver samples and from a selective effect of 7,8-benzojlavone on certain of the monooxygenases.
J. Kapitulnik, Ph.D., * P. J. Poppers, M.D., ** M. K. Buening, Ph.D., J. G. Fortner, M.D., *** and A. H. Conney, Ph.D. Nutley, N. J., and New York, N. Y. Department ~f Biochemistry and Drug Metabolism, Hoffmann-La Roche Inc., **Department of Anesthesiology, New York University School of Medicine, and ***Memorial Sloan-Kettering Cancer Cellter
Liver microsomes from rats, rabbits, and mice contain multiple forms of cytochrome P-4S0, the terminal oxidase of the enzyme system which metabolizes a wide variety of drugs, carcinogens and other environmental chemicals. 4 • 6. 10. 22, 23. 27, 28, 30 Many of these hemoproteins differ from one another in substrate specificities, antigenic properties, and moReceived for publication April 5, 1977. Accepted for publication June 17. 1977. Reprint requests to: Dr. A. H. Conney, Department of Biochemistry and Drug Metabolism. Hoffmann-LaRoche, Inc., Nutley, N. J. 07110. ·Present address: Department of Pharmacology, Hebrew Univer· sity Hadassah Medical School, Jerusalem, Israel.
lecular weights as determined by polyacrylamide gel electrophoresis. Although multiple forms of cytochrome P-4S0 have not yet been isolated and characterized from human liver, indirect evidence suggests that multiple monooxygenase systems do catalyze the oxidative metabolism of drugs and carcinogens in this tissue. 9, 20 An approach for determining the presence of mUltiple forms of cytochrome P-4S0 in rat liver is the use of chemicals that selectively affect certain monooxygenase activities. For example, 7,8-benzoflavone (BF, a-naphthoflavone) markedly inhibits the hydroxylation of the carcinogen benzo[aJpyrene by hepatic microsomes
475
476
Kapitulnik et al.
Clinical Pharmacology and Therapeutics
AUTOPSY LIVER
SURGICAL BIOPSY LIVER
800
300 ~
w.
J. Kapitulnik, Ph.D., * P. J. Poppers, M.D., ** M. K. Buening, Ph.D., J. G. Fortner, M.D., *** and A. H. Conney, Ph.D. Nutley, N. J., and New York, N. Y. Department ~f Biochemistry and Drug Metabolism, Hoffmann-La Roche Inc., **Department of Anesthesiology, New York University School of Medicine, and ***Memorial Sloan-Kettering Cancer Cellter
Liver microsomes from rats, rabbits, and mice contain multiple forms of cytochrome P-4S0, the terminal oxidase of the enzyme system which metabolizes a wide variety of drugs, carcinogens and other environmental chemicals. 4 • 6. 10. 22, 23. 27, 28, 30 Many of these hemoproteins differ from one another in substrate specificities, antigenic properties, and moReceived for publication April 5, 1977. Accepted for publication June 17. 1977. Reprint requests to: Dr. A. H. Conney, Department of Biochemistry and Drug Metabolism. Hoffmann-LaRoche, Inc., Nutley, N. J. 07110. ·Present address: Department of Pharmacology, Hebrew Univer· sity Hadassah Medical School, Jerusalem, Israel.
lecular weights as determined by polyacrylamide gel electrophoresis. Although multiple forms of cytochrome P-4S0 have not yet been isolated and characterized from human liver, indirect evidence suggests that multiple monooxygenase systems do catalyze the oxidative metabolism of drugs and carcinogens in this tissue. 9, 20 An approach for determining the presence of mUltiple forms of cytochrome P-4S0 in rat liver is the use of chemicals that selectively affect certain monooxygenase activities. For example, 7,8-benzoflavone (BF, a-naphthoflavone) markedly inhibits the hydroxylation of the carcinogen benzo[aJpyrene by hepatic microsomes
475
476
Kapitulnik et al.
Clinical Pharmacology and Therapeutics
AUTOPSY LIVER
SURGICAL BIOPSY LIVER
800
300 ~
w.
