The
sedative and
antiemetic drug thalidomide [α-(N-phthalimido)
glutarimide] was withdrawn in the early 1960s because of its potent teratogenic effects but was approved for the treatment of lesions associated with
leprosy in 1998 and
multiple myeloma in 2006. The mechanism of teratogenicity of
thalidomide still remains unclear, but it is well-established that metabolism of
thalidomide is important for both teratogenicity and
cancer treatment outcome.
Thalidomide is oxidized by various
cytochrome P450 (
P450) enzymes, the major one being P450 2C19, to 5-hydroxy-, 5'-hydroxy-, and dihydroxythalidomide. We previously reported that P450 3A4 oxidizes
thalidomide to the 5-hydroxy and dihydroxy metabolites, with the second oxidation step involving a reactive intermediate, possibly an arene
oxide, that can be trapped by
glutathione (GSH) to GSH adducts. We now show that the dihydroxythalidomide metabolite can be further oxidized to a
quinone intermediate. Human P450s 2J2, 2C18, and 4A11 were also found to oxidize
5-hydroxythalidomide to dihydroxy products. Unlike P450s 2C19 and 3A4, neither P450 2J2, 2C18, nor 4A11 oxidized
thalidomide itself. A recently approved amino analogue of
thalidomide,
pomalidomide (CC-4047, Actimid), was also oxidized by human liver microsomes and P450s 2C19, 3A4, and 2J2 to the corresponding
phthalimide ring-hydroxylated product.