High Bioactivators | Low Bioactivators | |||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
6HMa |
8HM
|
8JM
|
3JM
|
5JM
|
7JM
|
9JM
| ||||||
Control | 5.44 | 5.69 | 5.36 | 2.38 | 2.10 | 2.66 | 2.67 | |||||
- G.S. | 1.79 (-67)b | 1.06 (-81) | 2.04 (-61) | 1.65 (-31) | 0.69 (-67) | 0.50 (-81) | 1.78 (-33) | |||||
+ CO | 3.76 (-31) | 5.33 (-6.3) | 2.51 (-53) | 2.60 (+9.2) | 1.82 (-13) | N/A | N/A | |||||
+ mAB CYP2A6 | 3.58 (-34) | 4.33 (-24) | 3.74 (-30) | 2.52 (+5.9) | 1.26 (-40) | 4.41 (+66) | 1.59 (-40) | |||||
+ mAB CYP3A4/5 | 4.71 (-13) | 5.89 (+3.4) | 4.57 (-15) | 2.82 (+18) | 2.30 (+9.5) | 3.07 (+15) | 2.91 (+9.0) | |||||
+ mAB CYP2E1 | 4.64 (-15) | 3.79 (-33) | 5.79 (+8.0) | 3.38 (+42) | 1.58 (-25) | 2.95 (+11) | 2.06 (-23) | |||||
+ mAB CYP2B6 | 5.52 (+1.4) | 2.93 (-49) | 5.15 (-4.0) | 2.99 (+26) | 2.24 (+6.7) | 2.95 (+11) | 3.04 (+14) | |||||
+ 1.0 mM SKF-525A | 3.24 (-40) | 3.51 (-38) | 2.85 (-47) | 2.49 (+4.6) | 2.29 (+9.0) | N/A | N/A | |||||
+ 1.0 mM ABT | 3.62 (-33) | 2.53 (-56) | 3.55 (-34) | 1.87 (-21) | 1.54 (-27) | N/A | N/A | |||||
+ 5.0 mM ABT | 1.18 (-78) | 1.00 (-82) | 1.73 (-68) | 0.61 (-74) | ND (-100) | 0.24 (-91) | 1.22 (-54) | |||||
+ 2.5 μM 8-MS (CYP2A6)c | 4.12 (-24) | 4.27 (-25) | 3.69 (-31) | 3.11 (+31) | 4.53 (+116) | 2.27 (-15) | 1.99 (-25) | |||||
+ 50 μM TAO (CYP3A) | 4.51 (-17) | 3.52 (-38) | 5.14 (-4.1) | 1.98 (-17) | 3.39 (+61) | 3.22 (+21) | 4.54 (+70) | |||||
+ 3.0 μM ORP (CYP2B6) | 5.83 (+7) | 2.82 (-50) | 5.21 (-2.8) | 3.04 (+28) | 2.38 (+13) | 2.97 (+12) | 3.93 (+47) | |||||
+ 10 μM αMB (CYP2B6) | 4.27 (-22) | 4.12 (-28) | 5.51 (+2.8) | 2.35 (-1.3) | 2.69 (+28) | 2.56 (-3.8) | 2.55 (-4.5) | |||||
+ 10 μM BBT (CYP2B6) | N/A | N/A | 5.40 (+0.7) | 2.46 (+3.4) | 3.55 (+69) | N/A | 2.96 (+11) | |||||
+ 10 μM NDGA (LOX) | 4.53 (-17) | 4.25 (-25) | 5.27 (-1.7) | 2.73 (+15) | 3.69 (+76) | 1.56 (-41) | 2.03 (-24) | |||||
+ 10 μM INDO (PHS)
|
4.95 (-9)
|
5.89 (+3.4)
|
4.78 (-11)
|
2.24 (-5.9)
|
2.39 (+14)
|
3.07 (+15)
|
2.13 (-20)
|
-, incubations in the absence of; +, incubations in the presence of; G.S., NADPH-generating system; mAb, monoclonal inhibitory antibody; ND, not detectable; N/A, not available due to limited microsomal sample
↵ a Microsomes are assigned codes for patient confidentiality
↵ b Data are presented as the sum of four α-hydroxylation endpoint metabolites × 103; numbers in parentheses represent percentage change in NNK total bioactivation
↵ c Target biotransformation enzyme of chemical inhibitor