[Activity and induction of CYP2B, CYP2C, and CYP3A in tissues of cyclophosphane-sensitive and resistant neoplasms and the liver of neoplasm-carrying mice].
The activities of three cytochrome P450 families involved in metabolic transformation of cyclophosphamide (CP) (CYP2B and CYP2C responsible for metabolic activation of CP and CYP3A responsible for inactivation of CP) have been investigated in lymphosarcoma and liver microsomes of tumor-bearing CBA mice. Two strains of mouse lymphosarcoma distinguished by their sensitivity to cytostatic action of CP were used in this study for implantation in mice femur muscle. There was certain relationship between CP resistance of lymphosarcoma and tumor P450s activity. CYP2B, CYP2C and CYP3A activities in the CP sensitive tumor were comparable to those in liver, and CYP2B, CYP2C were induced by phenobarbital and dexamethasone. CYP2B and CYP2C in the CP resistant tumor were inactive and only slightly induced by dexamethasone. CYP3A activity was lower than in LS tumor and unchanged during drug treatment. Implantation of LS and RLS tumor in mice caused different effects on P450 activities. LS insignificantly influenced liver CYP2B, CYP2C and CYP3A activities and their inducibility by phenobarbital and dexamethasone was similar to that obtained in liver of mice without tumor. At the same time, CYP2B and CYP2C activity in liver of RLS-bearing mice were essentially reduced, the activity CYP3A remained unchanged, and inducibility of CYP2B, CYP2C and CYP3A by phenobarbital and dexamethasone was similar to that in liver of mice without tumor. These results prove the role of cytochromes P450 activating CP in formation drug resistant phenotype of mice lymphosarcoma and suggest possibility of overcoming of this resistance using cytochrome P450 inducers.
Grishanov
A Iu
AIu
Institute of Molecular Biology and Biophysics, Siberian Branch of Russian Academy of Medical Sciences, Timakova str., 2, Novosibirsk, 630117, Russia. agrish@cyber.ma.nsc.ru
Kaledin
V I
VI
Zueva
T V
TV
Nekhoroshkova
E K
EK
Nikolin
V P
VP
Liakhovich
V V
VV
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis / Q000378:metabolism*; D003520:Cyclophosphamide / Q000494:pharmacology* / Q000627:therapeutic use; D019362:Cytochrome P-450 CYP2B1 / Q000096:biosynthesis / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D004790:Enzyme Induction; D008113:Liver Neoplasms / Q000188:drug therapy / Q000201:enzymology*; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy / Q000201:enzymology*; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA; D008861:Microsomes / Q000201:enzymology; D009368:Neoplasm Transplantation; D010089:Oxidoreductases, N-Demethylating / Q000096:biosynthesis / Q000378:metabolism*
D000970:Antineoplastic Agents; C400322:cytochrome P-450 CYP2C subfamily; D003520:Cyclophosphamide; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; D019362:Cytochrome P-450 CYP2B1; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating