CYP Form | ABT-761 Hydroxylation | ABT-438 Hydroxylation | ||||
---|---|---|---|---|---|---|
Rate | Normalized Rate | Proportion | Rate | Normalized Rate | Proportion | |
pmol/hr/pmol | pmol/hr/mg | % of total | pmol/hr/pmol | pmol/hr/mg | % of total | |
1A2 | 0.1 | 3.4 | 2.3 | 0.1 | 4.2 | 0.8 |
2A6 | ND2-a | ND | ||||
2E1 | 0.1 | 1.5 | 1.0 | 0.2 | 4.8 | 0.9 |
2D6-Val374 | 0.4 | 2.1 | 1.4 | 1.3 | 6.6 | 1.3 |
2C9 | 0.6 | 28 | 19 | 1.0 | 47 | 9.1 |
3A4 | 1.0 | 99 | 66 | 4.7 | 446 | 86 |
2C19 | 1.3 | ≤15 | ≤9.9 | 0.8 | ≤8.3 | 1.6 |
Control2-b | ND | ND | ||||
Total2-c | 149 | 517 |
Hydroxylation of ABT-761 or ABT-438 (10 μM) in the presence of each CYP form (picomoles per hour per picomole of CYP) was normalized with respect to the nominal level of each CYP form present in native human liver microsomes (Shimada et al., 1994; Lecoeuret al., 1994), as follows: CYP1A2, 42 pmol/mg; CYP2C19, ≤11 pmol/mg; CYP3A4 (CYP3A5 assumed to be absent), 96 pmol/mg; CYP2D6, 5.0 pmol/mg; CYP2E1, 22 pmol/mg; CYP2A6, 14 pmol/mg; CYP2C9 (80% of total CYP2C protein), 49 pmol/mg; total CYP2C (CYP2C18, CYP2C9, CYP2C8, and CYP2C19), 60 pmol/mg. The specific content of total (spectrally detectable) CYP was assumed to be 300 pmol/mg. Normalized rates are expressed as picomoles per hour per milligram of microsomal protein.
↵2-a ND, no activity detected.
↵2-b Microsomes prepared from cells devoid of CYP.
↵2-c Sum of normalized rates.