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In vitro metabolism of DADS
by rat and human subcellular fractions
Results in rat presented
Results in human similar with the same metabolites
- Unité de Toxicologie Alimentaire - Dijon
In vitro metabolism of DADS in rat
DADS
cofactors
ultracentrifugation
HPLC-UV
microsomes
subcellular fractions
cytosols
- Unité de Toxicologie Alimentaire - Dijon
S
S
DADS
CYP 2B1/2
CYP 2E1
FMO
SH
AM
allyl mercaptan
GST
S
glutathione
AGS
allyl glutathionyl sulfide
O
S
S
DADSO
- Unité de Toxicologie Alimentaire - Dijon
products
Km
Vmax
Vmax/Km
nmole
nmol/min/mg prt
DADSO
0.86 ± 0.12
0.47 ± 0.12
1.83
AGS + AM
9.03 ± 2.56
0.25 ± 0.04
0.03

DADS  DADSO
products
monooxigenase
nmol/min/mg prt
GST
monooxygenase + GST
nmol/min/mg prt
nmol/min/mg prt
DADSO
1.82 ± 0.20
n.d.
n.d.
AM
n.d.
6.18 ± 0.23
11.00 ± 1.67
AGS
n.d.
0.21 ± 0.01
0.21 ± 0.01

DADS  DADSO + AM + AGS
- Unité de Toxicologie Alimentaire - Dijon
Isolated rat perfused liver
liver
collected bile
- Unité de Toxicologie Alimentaire - Dijon
Single dose pharmacokinetic parameters for DADS in an isolated perfused rat liver.
kel (min-1)
AUC0- (min.mmol/l)
t1/2 (min)
Clearance (ml/min)
Volume of distribution (ml)
0.13 ± 0.03
4.77 ± 0.80
6.09 ± 1.26
34.22 ± 5.6
311.9 ± 0.08
- Unité de Toxicologie Alimentaire - Dijon
nonane
60000
11.34
55000
AMSO2
50000
25.61
45000
AMS
40000
p-Cymène
6.15
17.64
35000
AMSO
30000
22.56
25000
20000
15000
10000
AM
5000
3.66
DADS
20.72
0
4
6
8
10
12
14
16
18
20
22
24
26
Time (min)
Total Ionic Current chromatogram of the extract of liver, perfused with
DADS, obtained on GC-MS.
- Unité de Toxicologie Alimentaire - Dijon
O
Compounds obtained in presence of subcellular fractions
S
Compounds obtained in an isolated perfused liver
O
AMSO2 allyl methyl sulfone
O
S
AMSO allyl methyl sulfoxide
S
S
MT
S
AMS allyl methyl sulfide
DADS
SH
CYP 2B1/2
CYP 2E1
FMO
AM allyl mercaptan
GST
S
glutathione
AGS allyl glutathionyl sulfide
O
S
S
DADSO
- Unité de Toxicologie Alimentaire - Dijon
DADS:

short half live time
many metabolites
Which is the real active molecule in vivo ?
- Unité de Toxicologie Alimentaire - Dijon