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[Cancer Research 59, 91-98, January 1, 1999]
© 1999 American Association for Cancer Research
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[Cancer Research 59, 91-98, January 1, 1999]
© 1999 American Association for Cancer Research

Carcinogenesis

Depentylation of [3H-pentyl]Methyl-n-amylnitrosamine by Rat Esophageal and Liver Microsomes and by Rat and Human Cytochrome P450 Isoforms1

Sheng C. Chen, Xiaojie Wang, Guoping Xu, Lin Zhou, Jonathan L. Vennerstrom, Frank Gonzalez, Harry V. Gelboin and Sidney S. Mirvish2

Eppley Institute for Research in Cancer [S. C. C., X. W., G. X., L. Z., S. S. M.], and Departments of Pharmaceutical Sciences [J. L. V., S. S. M.] and Biochemistry and Molecular Biology [S. S. M.], University of Nebraska Medical Center, Omaha, Nebraska 68198-6805, and National Cancer Institute, Bethesda, Maryland 20892 [F. G., H. V. G.]

Methyl-n-amylnitrosamine (MNAN) induces esophageal cancer in rats, probably involving activation by cytochromes P450. We studied the metabolic depentylation of MNAN. [3H-4,5-pentyl]MNAN and [3H-2,3-pentyl]MNAN were synthesized, purified, and incubated with rat esophageal microsomes (REM) or rat liver microsomes (RLM) to give [3H]pentaldehyde (depentylation), an indicator of MNAN activation. [3H]Pentaldehyde was determined by high-performance liquid chromatography of its 2,4-dinitrophenylhydrazone. Adding 5 mM semicarbazide to incubations increased the observed depentylation (except that due to CYP2E1) by >60%. MNAN depentylation by REM and uninduced and induced RLM showed Km values of 64, 610, and 170–330 µM, respectively (Vmax: 20, 220, and 160–1270 pmol/mg protein/min, respectively). The depentylation of 100 µM MNAN by REM was inhibited 98% by CO and 65% by coumarin preincubated for 15 min with REM (Ki, 120 µM) but was unaffected by antibodies inhibitory to various P450s. MNAN inhibited coumarin 7-hydroxylation by RLM and CYP2A6 (Ki, 3000 and 320 µM, respectively). REM showed slight coumarin 7-hydroxylase activity. MNAN depentylation by RLM was 41% inhibited by an antibody to CYP2C11. Km for rat CYP2E1, human CYP2E1, and human CYP2A6 was 210, 115, and 17 µM, respectively (Vmax: 900, 570, and 120 pmol/nmol P450/min, respectively). We conclude that MNAN activation by REM is probably due to a P450 related to CYP2A3, a rodent nasal P450.




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HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online
Copyright © 1999 by the American Association for Cancer Research.