title: Comparison of substrate metabolism by cytochromes P450 2B1, 2B4, and 2B6: relationship of heme spin state, catalysis, and the effects of cytochrome b5.
abstract: The metabolism of selected substrates by cytochromes P450 (P450) 2B1, 2B4, and 2B6 was compared, and the effects of cytochrome b(5) (b(5)) on these reactions were assessed. There did not appear to be any trends regarding the effects of b(5) when the metabolism of a given substrate by the different P450 enzymes was compared. The changes in spin states of the P450 enzymes as a result of interactions with substrates and cytochrome b(5) were also determined. Only P450 2B4 demonstrated a relationship between spin state, reaction coupling and b(5) effects. The rates of benzphetamine and 7-ethoxy-4-trifluoromethylcoumarin metabolism by the three enzymes could be correlated with the proportions of high spin heme. Similarly, the proportion of reaction coupling during the metabolism of selected substrates was approximately equal to the proportion of high spin P450. The data are interpreted to indicate that a P450 conformational equilibrium coordinately regulates catalysis and spin state changes.
authors.affiliation: Merck Research Laboratories, P.O. Box 2000, Mail Stop RY80L-109, Rahway, NJ 07065, USA. james_reed@merck.com
authors.forename: James R
authors.initials: JR
authors.lastname: Reed
authors.forename: Paul F
authors.initials: PF
authors.lastname: Hollenberg
mesh_terms: D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000737:chemistry* / Q000378:metabolism; D001589:Benzphetamine / Q000378:metabolism; D002384:Catalysis; D003374:Coumarins / Q000378:metabolism; D019362:Cytochrome P-450 CYP2B1 / Q000737:chemistry / Q000378:metabolism; D065702:Cytochrome P-450 CYP2B6; D000072467:Cytochrome P450 Family 2; D015786:Cytochromes b5 / Q000737:chemistry; D004583:Electrons; D006418:Heme / Q000737:chemistry; D008297:Male; D010089:Oxidoreductases, N-Demethylating; D011487:Protein Conformation; D011817:Rabbits; D051381:Rats; D020318:Rats, Long-Evans
chemical_list: D003374:Coumarins; D001589:Benzphetamine; C056033:7-ethoxy-4-trifluoromethylcoumarin; D006418:Heme; D015786:Cytochromes b5; D001189:Aryl Hydrocarbon Hydroxylases; D019362:Cytochrome P-450 CYP2B1; D065702:Cytochrome P-450 CYP2B6; D000072467:Cytochrome P450 Family 2; C465241:cytochrome P-450 CYP2B4 (rabbit); D010089:Oxidoreductases, N-Demethylating