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5.05.2.1.6 Other cytochrome P450 oxidative reactions

5.05.2.1.6.1 Oxidative dehydrogenation

The anticonvulsant valproic acid (101) undergoes normal cytochrome P450-catalyzed transformation, to generate the o and o-1 hydroxylated metabolites, (102 and 103, respectively; Scheme 9). However, the unsaturated substrate, 4-ene valproic acid (104), is also produced, suggesting product partitioning between the alcohol and alkene. While 104 is a minor metabolic product, its formation is important both from a mechanistic perspective and from the fact that it is toxic. Using selectively deuterated valproic acid analogs, Rettie et al.

established that 104 forms in competition with 103 after initial abstraction of a hydrogen atom from the o-1 carbon, to form the radical 105. Abstraction of a o-hydrogen atom to form the radical 106 only leads to 102.

Similarly, testosterone (107) is oxidized by CYP2A1 to four metabolites,

7a-hydroxy- and 6a-hydroxytestos-

terone (108 and 109, respectively), D6-testosterone (110), and D6-testosterone epoxide (111) (Scheme 10), the epoxide being formed from further oxidation of 110. Again using selectively deuterated analogs, Korzekwa et al.141 established that 110 was formed in competition with 109 after initial hydrogen atom abstraction from C-6 to form the radical 112. Little if any 108 formed upon initial hydrogen abstraction from C-7.

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