Disposition and metabolism of dipropyl disulphide in vivo in rat

Article abstract of DOI:10.1080/00498250701742645

The metabolism of dipropyl disulphide (DPDS), a sulphur compound from onion, was investigated in vivo in the rat. A single dose (200 mg kg-1) was administered by gastric intubation and the time courses of DPDS and its metabolites were followed over 48 h by gas chromatography coupled with mass spectrometry in the stomach, intestine, liver, and blood. DPDS was detected in the stomach where it was transformed into propyl mercaptan, whereas the liver contained only traces of DPDS and none at all in the other examined organs. The metabolites methylpropyl sulphide, methylpropyl sulphoxide (MPSO), and methylpropyl sulphone (MPSO2) were sequentially formed in the liver. The route of elimination from the liver seemed to be mainly via the blood. The bile also participated in the excretory process, but only for MPSO2. The pharmacokinetic parameters were determined for all of the above compounds. Whereas the bioavailability of DPDS was very low (0.008 h mM), the areas under the curve were higher for the S-oxidized metabolites MPSO and MPSO2, i.e. 9.64 and 24.15 h mM, respectively. The half-lives for DPDS and its metabolites varied between 2.0 and 8.25 h, except for MPSO2, which had a half-life of 29.6 h. MPSO2 was the most abundant and persistent of these metabolites.

Full text of DOI:10.1080/00498250701742645

Xenobiotica, Vol. 38, No. 1, January 2008, 87–97
Disposition and metabolism of dipropyl disulphide
in vivo in rat
1
E. GERMAIN , E. SEMON , M.-H. SIESS , & C. TEYSSIER
2
1
1,3
1
2
UMR Toxicologie Alimentaire, UMR1129 Flaveur, vision et comportement du consommateur,
3
INRA, Dijon, France, and UR588 Am e´ lioration, g e´ n e´ tique et physiologie foresti e` res, INRA,
Orl e´ ans, France
(
Received 4 September 2007; revised 2 October 2007; accepted 11 October 2007)
Abstract
The metabolism of dipropyl disulphide (DPDS), a sulphur compound from onion, was investigated
ꢀ1
in vivo in the rat. A single dose (200 mg kg ) was administered by gastric intubation and the
time courses of DPDS and its metabolites were followed over 48 h by gas chromatography
coupled with mass spectrometry in the stomach, intestine, liver, and blood. DPDS was detected in
the stomach where it was transformed into propyl mercaptan, whereas the liver contained only traces
of DPDS and none at all in the other examined organs. The metabolites methylpropyl sulphide,
methylpropyl sulphoxide (MPSO), and methylpropyl sulphone (MPSO
in the liver. The route of elimination from the liver seemed to be mainly via the blood. The bile also
participated in the excretory process, but only for MPSO . The pharmacokinetic parameters were
determined for all of the above compounds. Whereas the bioavailability of DPDS was very low
0.008 h mM), the areas under the curve were higher for the S-oxidized metabolites MPSO
and MPSO , i.e. 9.64 and 24.15 h mM, respectively. The half-lives for DPDS and its metabolites
varied between 2.0 and 8.25 h, except for MPSO , which had a half-life of 29.6 h. MPSO was
2
) were sequentially formed
2
(
2
2
2
the most abundant and persistent of these metabolites.
Keywords: Allium, onion, metabolism, dipropyl disulphide, mercaptan, sulphoxide, sulphone
Introduction
Plants of Allium species such as onion and garlic are among the oldest of all cultivated
plants, have fascinated man since the earliest times, and have been used as foodstuffs and as
drugs in folk medicine (Rivlin 2001). More recently it is becoming increasingly evident
Correspondence: C. Teyssier, UR588 Amelioration, g e´ n e´ tique et physiologie foresti e` res, INRA, Avenue de la Pomme de Pin, BP
2
0619 Ardon, F ¼ 45160 Olivet, France. E-mail: Caroline.Teyssier@orleans.inra.fr
ISSN 0049-8254 print/ISSN 1366-5928 online ß 2008 Informa UK Ltd.
DOI: 10.1080/00498250701742645

8
8
E. Germain et al.
that they have beneficial effects on cardiovascular diseases and some cancers (Le Bon &
Siess 2000; Bianchini & Vainio 2001; Rahman 2001) and most of their properties have
been attributed to specific sulphur compounds present in high levels in these vegetables
(Lanzotti 2006). Sulphur compounds from garlic and onion have been shown to have
an impact on many processes involved in carcinogenesis as well as atherogenesis and anti-
inflammatory, antithrombic, hypotensive, hypolipidemic, antibacterial, antiviral, and
antifungal properties have been demonstrated (Augusti 1996; Bianchini & Vainio 2001;
Rahman 2001; Griffiths et al. 2002). Most experimental studies have focused on allyl
sulphides, mainly derived from garlic, whereas much less is known about alkyl sulphides,
which are present in other Allium species such as onion (Block et al. 1992) and leek
(Nielsen & Poll 2004).
Dipropyl disulphide (DPDS) (Figure 1) is the major polysulphide produced among a wide
range of sulphur compounds resulting from a series of chemical reactions. This chain of
reactions is initiated by the action of allinase on S-alk(en)yl-cysteine sulphoxides, the flavour
S
S
DPDS : dipropyl disulphide
O
S
S
DPDSO : dipropyl thiosulfinate
S
MPS : methylpropyl sulphide
O
S
MPSO : methylpropyl sulphoxide
O
S
O
MPSO : methylpropyl sulphone
2
Glu
Gly
Cys
S
PGS : propyl glutathione sulphide
SH
PM : propyl mercaptan
Figure 1. Molecular structures of sulphur compounds.

Metabolism of dipropyl disulphide in rat
89
precursors, after disruption or crushing of an onion bulb (Lancaster & Boland 1990). Up to
now little is known about the biotransformation of allyl and alkyl sulphides in animals and
man. The metabolism of monosulphides such as diallyl sulphide and dipropyl sulphide has
been studied in rats, where oxidation of the sulphur atom results in the production of
sulphoxides and sulphones (Brady et al. 1991; Chen et al. 1994; Nickson & Mitchell 1994).
Metabolism of disulphides, such as diallyl disulphide (DADS) and DPDS, have been
investigated more recently. In vitro, these compounds have also been reported to be
metabolized by sulphur oxidation. In the presence of rat liver subcellular fractions, the
metabolism of DPDS occurs by the oxidation of one atom of sulphur to give the
corresponding thiosulphinate DPDSO or by conjugation with glutathione mediated by
glutathione S-transferase to yield propylglutathione sulphide (PGS) and propyl mercaptan
(
PM) (Figure 1) (Teyssier & Siess 2000). With DADS, similar metabolites have been
observed in human and rat using subcellular fractions (Teyssier et al. 1999; Germain et al.
003). Ex vivo, in an isolated perfused rat liver, DPDS is transformed into PM,
2
methylpropyl sulphide (MPS), methylpropyl sulphoxide (MPSO), and methylpropyl
sulphone (MPSO ) (Figure 1) (Teyssier & Siess 2000). The latter authors hypothesized
2
that the methylation of PM to MPS and its further oxidation to MPSO occurred. Ex vivo,
2
DADS is transformed into allyl mercaptan, allylmethyl sulphide, allylmethyl sulphoxide, and
allylmethyl sulphone (Egen-Schwind et al. 1992; Germain et al. 2003), whereas in primary
rat hepatocytes the products of DADS metabolism are allyl mercaptan and allylmethyl
sulphide (Sheen et al. 1999). Germain et al. (2002) have studied the in vivo metabolism
of diallyl disulphide (DADS) and have also demonstrated extensive catabolism.
They identified allyl mercaptan, allylmethyl sulphide, allylmethyl sulphoxide and allylmethyl
sulphone as metabolites.
The in vitro metabolism of DPDS is well established in rat (Teyssier & Siess 2000),
but has to be confirmed in vivo before postulating any role of DPDS on health and disease.
The present study was undertaken to investigate the in vivo fate of DPDS and its metabolites
ꢀ1
in rats after a single oral administration of 200 mg of DPDS kg body weight. We compared
the metabolites detected with those observed in vitro and ex vivo. For this purpose
we analysed sulphur compound distribution in the stomach, intestine, plasma, and liver
tissues by a quantitative and sensitive gas chromatography coupled with mass spectrometry
(GC-MS) method which has already been validated (Martin-Lagos et al. 1995; Germain
et al. 2002), and we additionally determined their pharmacokinetic parameters.
Materials and methods
Chemicals
DPDS (purity 98%), PM, MPS, sodium metaperiodate, p-cymene and nonane were
purchased from Sigma Aldrich Chemical (L’Isle D’Abeau, France). All other chemicals
and reagents were of the highest commercial quality available. Dichloromethane was
distilled before use for solvent extractions.
Synthesis of MPSO and MPSO2
MPSO and MPSO were obtained by oxidation of MPS with sodium metaperiodate in
2
a methanolic solution thawed on ice overnight as already described (Furniss et al. 1989;

9
0
E. Germain et al.
Teyssier & Siess 2000). After extraction, the compounds were injected into gas
chromatography coupled with mass spectrometry (GC-MS) in order to assess their
structure by comparison with a library of spectra. The reaction was complete but gave
a mixture of MPSO (69.77%) and of MPSO (30.23%) as estimated by GC-MS.
2
Drug administration
Male 6-week-old Wistar rats (n ¼ 24, average weight 263 ꢁ 19 g) were purchased
from Janvier (Le Genest, Saint Isle, France). Rats were housed in individual stainless-
wire cages. They were fed ad libitum with a semi-synthetic diet consisting of (on a dry
matter basis) 18% casein, 43% starch, 21% saccharose, 5% corn oil, 2% cellulose,
5% mineral mixture, and 1% vitamin mixture for 1 week before the beginning of the
experiment. Water was added to the diet in the ratio 50 g water/100 g dry matter. The liquid
diet was prepared daily. Drinking water was provided ad libitum. The animals were fasted for
1
8 h before and 5 h after drug administration. DPDS, dissolved in corn oil, was administered
ꢀ
1
by gastric intubation at a dose of 200 mg kg body weight. This dose was selected because
it is equivalent to dose consumed per rat and per day in previous experiments showing
an inhibiting effect of DPDS on the genotoxicity of carcinogens (Guyonnet et al. 2001).
Three animals were included as negative controls in order to check that no sulphur
compounds were detectable in their tissues. After oral administration, animals were
maintained separately in metabolic cages. In each experiment, three animals were killed
by exsanguination under anaesthesia (isoflurane 2.5% in oxygen) at 1, 2, 4, 8, 24, 36,
and 48 h after oral dosing. Blood samples were withdrawn into tubes containing EDTA.
Livers, stomachs, and intestines (40 cm long from the stomach) were removed, weighed,
ꢂ
and stored at ꢀ20 C for a few days until further analysis. Blood was immediately
ꢂ
centrifuged and plasma was stored at ꢀ20 C for a few days before analysis. Subsequently,
the tissues were thawed on ice and were extracted as previously described (Germain et al.
2
003). Briefly, stomachs, intestines and livers were homogenized in distilled water.
ꢀ
1
p-Cymene in ethanol solution (0.17 mg ml ) was added as an internal standard. After
trichloroacetic acid protein precipitation, the homogenate was centrifuged and the
supernatant extracted three times with dichloromethane. The same protocol without
homogenization was used for the plasma samples. The samples were then concentrated
by evaporation under a nitrogen stream to a final volume of 500 ml. To this volume, 100 ml
of nonane dissolved in dichloromethane (0.147 mg ml ) was added in order to
standardize the sample concentration and an aliquot of 1 ml was injected into the gas
chromatograph under the conditions described below.
ꢀ
1
GC-MS conditions for organosulphur compounds analysis
GC-MS was carried out using a 5973N Mass Selective Detector coupled to a 6890 gas
TM
chromatograph (Agilent Technologies, Massy, France) equipped with a DB 1701
capillary column (30 m ꢃ 0.32 mm i.d., 1 mm film thickness) (J&W Scientific, Folsom,
CA, USA). Samples were injected in splitless mode into an injection port maintained
ꢂ
ꢀ1
at 200 C. Helium was the carrier gas with a 35 cm s constant velocity. The oven was
ꢂ
ꢂ
ꢂ
ꢀ1
programmed from 35 C (2 min) to 220 C at a linear rate of 5 C min . Mass spectra were
obtained in a positive-ion mode with an electronic impact of 70 eV. Each sample was
analysed twice. First acquisition, GC-MS was used in scan mode from m/z 29 to 300 amu in
order to ascertain the identification of compounds by comparison with standards based

Metabolism of dipropyl disulphide in rat
91
on their retention time and their spectra. Second acquisition, GC-MS was used in selected
ion-monitoring (SIM) mode. The quantification of PM, MPS, MPSO, MPSO and DPDS
2
was achieved by monitoring the ions at m/z 76, 90, 106, 81 and 150, respectively. The purity
was continuously checked by the ratio between the quantifying ion and another one,
specific for each compound.
Quantitative determination of the organosulphur compounds
For each sulphur compound the sensitivity and linearity of the GC-MS detector used in the
SIM mode was calculated from a series of standard solutions dissolved in dichloromethane.
The concentration of each sulphur compound in the biological samples (600 ml) was
calculated according to the following equation:
areasulphurcompound
1
1
Concentration ðmMÞ¼
ꢃ
ꢃ
areapꢀcymeneꢃarea nonane responsecoeffecient yieldof extraction
The response coefficient (a) was calculated from the curve:
y ¼ ax þ b,
where y is the adjusted area (with the areas of p-cymene and nonane) of the quantified ion; x
is the concentration of the compound (mM) in the vial; and b is the detection limit.
The extraction yield was determined for each sulphur compound in each analysed tissue and
corresponded to the percentage of extracted compound from the tissue. From the
concentration of sulphur compounds, the quantity (mmol) of sulphur compounds per
organ was calculated. The limit of detection varied depending on the sulphur compound
from 0.33 nmol (MPSO ) to 3.42 nmol (PM). Results are presented as means of three rats.
2
Pharmacokinetic analysis
Pharmacokinetic parameters were determined from plasma concentrations using a
Õ
non-compartmental method and were calculated using Kinetica software (InnaPhase,
Champs sur Marne, France). The area under the plasma concentration–time curve (AUC)
was computed using the trapezoidal rule, when C > C ꢀ 1. The elimination half-life (t1/2)
n
n
was calculated as:
ln 2
t1=2 ¼ L z
,
where L is the elimination rate constant. The plasma clearance (Cl ) was calculated as:
p
z
dose
Cl p
¼
:
AUC
Tmax corresponded to the time at which the maximum concentration was reached (Cmax).
Results
Identification of the detected products
Figure 2 represents a typical GC-MS chromatogram (total ion current) observed in the liver
4
h after DPDS administration. When DPDS was administered to rats, this molecule

9
2
E. Germain et al.
2
2
1
1
1
1
1
2000
0000
8000
6000
4000
2000
0000
PM
3.76
MPS
6.45
nonane
11.34
MPSO
22.67
MPSO2
26.63
p-cymene
17.67
8
6
4
2
000
000
000
000
0
DPDS
1.16
2
4
.0
6.0
8.0 10.0 12.0 14.0 16.0 18.0 20.0 22.0 24.0 26.0 28.0 30.0
Time (min)
Figure 2. Total ionic current chromatogram of extracted liver at 4 h obtained on GC-MS. Numbers
under the compound names are retention times.
was detected by GC-MS in all extracted tissues (stomach, intestine, liver and plasma).
PM, MPS, MPSO, and MPSO2 were additional metabolites and were identified by
comparing their retention times and fragmentation spectra with those of standards and/or
those derived from a spectra library (Wiley library). Figure 3 presents, for each organ,
the quantities of these sulphur compounds as a function of time.
Profile of DPDS in the organs examined
One hour after administration, DPDS was mainly detected in the stomach (Figure 3A).
The absorption of DPDS is probably almost complete in this organ, as the DPDS quantity in
the intestine is quite negligible (less than 0.01 mmol in the intestine compared with
more than 50 mmol in the stomach at 2 h). For these two organs, the amount of DPDS
declined rapidly between 4 and 8 h after administration.
Profile of DPDS metabolites in the organs examined
In each organ, the metabolites were detected with various rates of appearance and
different concentration–time profiles. In the stomach, DPDS and PM were detected very
early (from the first hour after administration). The DPDS concentration–time profile was
similar to that of PM. However, the concentrations of DPDS were higher than the
concentrations of PM (Figure 3A). In the liver, MPS appeared first and transiently and
then followed by the appearance of MPSO, and MPSO . Whereas PM, MPS and MPSO
2
were detected 1 h after administration of DPDS, MPSO appeared only at 2 h and its
2
concentration gradually increased until 24 h and then gradually decreased. At 48 h its
concentration was comparable to that observed at 8 h. The slow appearance of MPSO in
2
the liver suggested a slow biotransformation from its precursor MPSO. MPSO2 also
demonstrated a transient high concentration in the liver. In plasma (Figure 3D),
PM reached a maximal concentration very early whereas the maximal concentration
of MPSO was at 8 h, and that of MPSO was delayed to 24 h. In the stomach and in
2

Metabolism of dipropyl disulphide in rat
93
A/ stomach
60
50
40
30
20
10
0
1
0
8
6
4
2
0
0
1
2
3
4
5
6
hours
0
10
20
30
4
0
hours
B/ intestine
7
6
5
4
3
2
1
0
1
0
0
.0
.5
.0
0
1
2
3
4
5
6
hours
0
10
20
30
4
0
hours
C/ liver
60
50
40
30
20
10
0
10
8
6
4
2
0
0
1
2
3
4
5
6
hours
0
10
20
30
4
0
hours
D/ plasma
7
2
.0
.5
6
5
4
3
2
1
0
1
1.0
0.5
0.0
0
1
2
3
4
5
6
hours
0
10
20
30
4
0
Figure 3. Quantity of volatile metabolites during the 48-h period in the stomach, intestine, liver,
ꢀ1
and plasma after one oral administration of 200 mg kg of DPDS to male rats. DPDS,
PM, MPS, MPSO, MPSO , Results are the mean of three rats.
2

9
4
E. Germain et al.
1000
100
10
1
0
.1
.01
.001
0
0
0
10
20
30
40
50
Time (h)
DPDS
PM
MPS
MPSO
MPSO2
Figure 4. Plasma concentration–time curve of metabolites of DPDS after one oral administration to
male rats. Data are means of three rats ꢁ standard deviation.
the intestine, the maximal concentrations were at 8 h for MPSO and at 24 h for MPSO2.
The presence of these metabolites in the digestive tract at this time was probably caused
by the introduction of these compounds at this time rather than an in situ metabolic
transformation of DPDS or PM. The quantity of MPSO2 in stomach and intestine
represented 7.9 and 9.6%, respectively, of that of the liver.
Pharmacokinetic parameters
The plasma concentration–time curves of DPDS and its metabolites after oral administra-
tion to rats are shown in Figure 4 and the pharmacokinetic parameters are summarized
in Table I. All parameters were determined only for DPDS as the plasmatic clearance could
only be determined for the administered compound. The t1/2 (between 2 and 8 h) were quite
similar for all metabolites, except MPSO , whose t was 30 h. The bioavailability, measured
2
1/2
by the AUC of each compound, was very low for DPDS (0.008 h mM), because it was
immediately transformed after administration. The AUC values were higher for MPSO and
MPSO with values of 9.64 and 24.15 h mM, respectively. The T
values for the majority
of these sulphur compounds were short (between 4 and 8 h) indicating the non-persistence
2
max
of these compounds in the plasma, whereas the Tmax for MPSO was delayed to 24 h.
2
Discussion
The present study was carried out in order to investigate the in vivo biotransformation
of DPDS after a single oral administration to rats. PM, MPS, MPSO, and MPSO were
2
identified as DPDS metabolites in the stomach, intestine, liver, and plasma. Based
upon their plasma concentrations, their pharmacokinetic parameters were determined.
These compounds seemed to be rapidly metabolized or eliminated within a few hours, with a

Metabolism of dipropyl disulphide in rat
95
Table I. Pharmacokinetics parameters of dipropyl disulphide (DPDS) and its metabolites after a single oral
administration of DPDS in the rat.
Dipropyl
Propyl
Methylpropyl
Methylpropyl
Methylpropyl
disulphide (DPDS) mercaptan (PM) sulphide (MPS) sulphoxide (MPSO) sulphone (MPSO
2
)
t
1/2 (h)
max (mM)
max (h)
AUCtotal (h mM)
8.25
0.001
4
2.08
0.263
8
6.30
0.145
8
5.85
0.670
8
29.57
0.419
24
C
T
0.008
39.57
3.44
n.c.
2.07
n.c.
9.64
n.c.
24.15
n.c.
ꢀ
1
Cl (l h )
p
n.c., not calculated.
Parameters were calculated from three rats.
rate of biotransformation in rats similar to other sulphur compounds originating
from Allium. The t1/2’s of vinyldithiins, from garlic, were about 5 h. They were detected
in many tissues over a period of 24 h, but the maximal serum concentration was observed
within the 30 first min after ingestion (Egen-Schwind et al. 1992). After DADS
administration to rats, the t1/2’s of the sulphur metabolites were reported to be between
4
.0 and 8.5 h with a Tmax of 24 or 48 h (Germain et al. 2002).
The uptake of DPDS in the liver was observed only during the first hours after
dosing. This level did not exceed 1% of the DPDS level in the stomach. The fact that DPDS
was hardly detected outside the digestive tract could be linked to its metabolism. Indeed,
the t1/2 of DPDS was about 8 h. PM was detected in the stomach at 1 h post-dosing.
As DPDS was administered by gastric intubation, PM could result only from a
transformation of DPDS in this organ. Glutathione S-transferases have previously been
identified as catalysing the formation in vitro of PM from DPDS (Teyssier & Siess 2000).
The presence of these enzymes in the stomach (Pinkus et al. 1977) could explain the
formation of PM. The AUCtot and Cmax of DPDS (0.008 h mM and 0.001 mM,
respectively) are lower than the corresponding pharmacokinetic parameters of PM (3.44 h
mM and 0.263 mM, respectively). These parameters, in association with the persistence of
DPDS and PM in the stomach, indicate that there is a low absorption of DPDS in blood,
but a rapid one of PM. In stomach, the concentration of DPDS was higher than the
concentration of its metabolite PM and the decrease in PM was not compensated for by
the appearance of a new metabolite in the stomach. This suggested that (1) DPDS was
almost totally transformed into PM and (2) that PM, once formed, was directly and
rapidly absorbed though the stomach wall.
The present data show that DPDS is transformed into PM, MPS, MPSO, and MPSO2.
Among these metabolites, MPSO and especially MPSO are the major and more persistent
2
volatile metabolites found in all tissues examined. MPSO2 appears to be the ultimate
metabolite since no new metabolite was detected when its level decreased. We have
previously proposed a scheme for the in vitro metabolism of DPDS based on subcellular
fractions and isolated perfused liver experiments (Teyssier & Siess 2000) and the
pharmacokinetics described in the present study validate this hypothesis. PM is the first
detectable metabolite of DPDS which is sequentially transformed into PM, then MPS,
then MPSO, and finally to MPSO . This agrees with the chemical stability of the hydrophilic
2
sulphone, which is therefore readily detected in the urine. This conclusion is supported
by the work of Nickson et al. (1995), who only detected dipropyl sulphone in
the urine of rats after oral ingestion of dipropyl sulphoxide. In the case of
administration of DADS to rats, the ultimate metabolite was also a sulphone detected in
the urine (Germain et al. 2002).

9
6
E. Germain et al.
In agreement with the literature, the present study emphasizes that the liver plays a
major role in the in vivo metabolism of DPDS. All metabolites of DPDS, excepted PM,
first appeared in this latter organ. Moreover, they have been previously identified in rat
liver perfused with DPDS (Teyssier & Siess 2000), therefore they are probably formed in
this organ. The slow elimination of MPSO (t ¼ 29.57 h) and the level of this molecule
2
1/2
in the liver suggests a role for this organ in the storage of sulphur compounds. Compounds
containing a sulphoxide or sulphone moiety may interact strongly with their surrounding
environment (via hydrogen bond formation, etc.) and thereby delay their excretion
(Mitchell 1988). At the same experimental time, the S-oxidized metabolites in the stomach
and the intestine appeared in the absence of potential substrate in these organs and
after their formation in the liver (Figure 3A and B). This indicated elimination from the liver
of a fraction of MPSO and MPSO by the bile. In fact, elimination was higher via the
2
plasma for MPSO, and via the intestine for MPSO (70.8% of the elimination). With our
2
experimental protocol, it was not possible to identify an enterohepatic cycle, but the
latter might explain the persistence of MPSO in the body. Nickson & Mitchell (1996)
2
demonstrate the existence of such a cycle for the dipropyl sulphone, a very similar sulphur
compound. Dipropyl sulphone is below the generally assumed minimum threshold
molecular weight required for a notable biliary excretion. The hypothesis of the authors
was the chemical properties of the S-O bond which could end at molecular stacking
increasing the apparent molecular weight. Even if one could explain this by a phenomenon
of molecular stacking, the biliary excretion of MPSO , we cannot explain why this is not
2
also the case for MPSO which is eliminated at a rate of 85.6% by the plasma.
This study has clearly established the presence of volatile metabolites in several
organs after DPDS ingestion in the rat. The formation of other metabolites cannot be
ruled out, which could not be detected using the analysis method. In particular, it has been
reported that several glutathione conjugates are formed in vivo from diallyl sulphide
(Jin & Baillie 1997) and in vitro from DADS and DPDS (Teyssier & Siess 2000; Germain
et al. 2003). This conjugation could also happen during the in vivo DPDS metabolic
process. Hence, if such conjugates actually exist, it would be of major interest to compare
their levels with those of MPSO and MPSO2.
In conclusion, it has been confirmed that the metabolites PM and MPS and MPSO already
2
observed in vitro are also in vivo metabolites of DPDS and MPSO has been identified as a new
and previously unreported metabolite of DPDS in rat, which has not been observed in any
previous study. DPDS has been shown to have anticarcinogenic, antimutagenic, and
hypolipidemic effects (Wattenberg et al. 1989; Liu & Yeh 2000; Guyonnet et al. 2001).
Nevertheless, due to the rapid metabolism described herein, DPDS seems to have no systemic
bioavailability after oral administration. Taking into account the time of exposure and
quantity of the different metabolites of DPDS, the S-oxidized compounds are certainly
involved in the beneficial effects ascribed to onion. Further studies are needed to assess the
biological effects of these two metabolites of DPDS. Finally, as DPDS and its metabolites are
probably biologically active component of Allium species, it would be of great interest to
explore the bioavailability and metabolism of such compounds in man.
References
Augusti KT. 1996. Therapeutic values of onion (Allium cepa L.) and garlic (Allium sativum L.). Indian Journal of
Experimental Biology 34:634–640.

Metabolism of dipropyl disulphide in rat
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Bianchini F, Vainio H. 2001. Allium vegetables and organosulfur compounds: Do they help prevent cancer?.
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