Disposition of diphenyl sulphoxide in rat

Article abstract of DOI:10.1080/004982598239281

1. Radiolabelled diphenyl sulphoxide (U-14C- or 35S-) was administered by gavage 1.0 mmol/kg body weight) to the adult male Wistar rat following an overnight fast. 2. For both labelled forms faeces was the major route of excretion of radioactivity (50%) w

Full text of DOI:10.1080/004982598239281

xenobiotica , 1998, vol. 28, no. 7, 715±722
Disposition of diphenyl sulphoxide in rat
S. C. MITCHELL,* J. GILLHAM, W. F. M. JACKSON,
S. L. PRESTON, E. R. PORTER and A. Q. ZHANG
Molecular Toxicology, Division of Biomedical Sciences, Imperial College School of
Medicine, Norfolk Place, London W2 1PG, UK
Received 30 January 1998
1. Radiolabelled diphenyl sulphoxide (U-14C- or 35S-) was administered by gavage
(1.0 mmol kg body weight) to the adult male Wistar rat following an overnight fast.
}
2. For both labelled forms faeces was the major route of excretion of radioactivity
(50 %) with substantial amounts still being voided during the third and fourth days (13 %).
Urinary elimination (42%) was similar during the ®rst (20 %) and second (17 %) days and
a small amount of radioactivity (7 %) was found within the carcass after 4 days.
3. Plasma data showed a peak concentration at 40 min (t ), a distribution half-life of
a
max
b
2 h (t" ) and an elimination half-life of 22.5 h (t" ). Biliary studies revealed that 16 % of the
dose traversed the bile duct during the ®rst day w# ith nearly half of this being excreted in the
®rst 8 h.
#
4. From urinary data, metabolism occurred via ring hydroxylation with subsequent
conjugate formation. Oxidation of the sulphur to form the sulphone also took place. No
evidence for sulphoxide reduction, cleavage of the ring structures or exclusion of the
sulphur was obtained.
Introduction
Diphenyl sulphoxide (1,1 -sulphinylbisbenzene) is a simple aromatic sulphoxide
´
that ®nds use, together with its parent sulphide, as an intermediate in chemical
synthesis especially in the plastics industry. The sulphoxide has both defoliant
(Goodhue and Tissot 1953) and fungicidal properties (Siegler and Childs 1947,
Esrolko 1949) but has negligible insecticidal activity when compared with the
sulphide (Beran et al. 1951). It has also been investigated, along with other
sulphoxides (Lavine 1935), as a tumour growth suppressant, but was without eåect
(Hammett 1942). Subcutaneous administration of diphenyl sulphoxide to mouse
has led to neurotoxic eåects including limb paralysis, convulsion and respiratory
suppression (Hammett 1942). The present investigations have been undertaken as,
to date, little is known concerning the fate of diphenyl sulphoxide within living
systems.
M aterials and m ethods
Chemicals
Diphenyl sulphide, diphenyl sulphoxide, diphenyl sulphone, benzene, sulphur, thionyl chloride,
hydrogen peroxide and anhydrous aluminium chloride were obtained from Aldrich Chemical Co. Ltd
(Dorset, UK). All other chemicals were of analytical grade and readily available within the laboratory.
[U-14C]-diphenyl sulphoxide was prepared by the thionation of [U-14C]-benzene (Sigma Chemical
Co, St Louis, MO, USA). Small amounts (c.0.2 g) of anhydrous aluminium chloride were stirred into an
ice-cooled mixture of [U-14C]-benzene (10 g, 128 mmol; 1 mCi) and thionyl chloride (3.8 g, 32 mmol)
until the evolution of hydrogen chloride ceased (c.6 g). The mixture was then re¯uxed for 30 min after
the addition of extra benzene (4 g, 51.2 mmol). On cooling, the mixture was poured into excess ice-water
* Author for correspondence.
.
’
1998 Taylor and Francis Ltd
0049±8254}98 $12 00

716
S. C. Mitchell et al.
and the precipitated yellow oil washed several times with water. Excess benzene was removed by
distillation and the residue recrystallized from petroleum ether (b.p. 60±80 ÊC) (Colby and McLoughlin
1887, Shriner et al. 1930).
The white crystalline substance (m.p. 69±70 ÊC uncorr. ; lit. 70±1 ÊC, Colby and McLoughlin 1887,
Shriner et al. 1930) gave a chemical analysis in agreement with the theoretical value (expected for
k
k
C
H
SO ; C 71.3, H 5.0 ; found C 71.1, H 5.2), UV peaks (ethanol) at
233 (loge 4.14) and
265
max
max
"# "!
Õ
Õ
(loge3.31), a strong IR band at c.1040 cm " (KBr) or c.1050 cm " (in CCl ) (S-O stretching) (Barnard et
%
al. 1949, Cymerman and Willis 1951) and a top mass ion at m z 202 (mol. wt. 202) (Bowie et al. 1966).
}
A
radiochemical purities
speci®c activity of 15.6 mCi mol (radiochemical yield 40 %) was obtained with chemical and
}
"
(see below). The compound was highly soluble in most organic solvents (except cold hexane, heptane and
99 % as determined by thin-layer (tlc) and capillary gas-liquid chromatography
petroleum ether) with a partition coeæcient (logP, octanol water) of 1.37.
}
[35S]-diphenyl sulphoxide was prepared in a similar manner via [35S]-diphenyl sulphide. Finely
powdered anhydrous aluminium chloride (4.2 g) was dispersed in dry benzene (10 g, 128 mmol; excess)
with constant stirring and [35S]-sulphur (1 g, 31.3 mmol ; Amersham International, Amersham, UK)
added slowly while the mixture was re¯uxed under a stream of nitrogen for 4 h . The radioactive
hydrogen sulphide evolved was removed by passing the gas, amid the nitrogen stream, through acidi®ed
potassium dichromate solution (turns orange to green) which was constantly renewed. Dilute
m
hydrochloric acid (8 ml, 1.5 ) was added to the cold re¯uxed mixture and the separated benzene layer
washed with water and dried over calcium chloride before being removed by distillation. Anhydrous
ethanol (16 ml) was added to the residue and the ®ltered liquid distilled under reduced pressure ; the
diphenyl sulphide coming over at 115 ÊC (3 mmHg) (1.1 g, 5.9 mmol; yield 19 % relative to sulphur)
(Boeseken 1905, Dougherty and Hammond 1935). Hydrogen peroxide (1 ml, 30 % by wt) was slowly
stirred into an ice-cold solution of [35S]-diphenyl sulphide (1 g, 5.3 mmol) in acetone (10 ml) and left for
24 h at room temperature. Following removal of the acetone under reduced pressure, the aqueous residue
was extracted with chloroform (33 5 ml) which was subsequently dried over anhydrous magnesium
sulphate. Removal of the chloroform and repeated recrystallization from petroleum ether (b.p.
60±80 ÊC) chloroform (95 5 v v) aåorded white crystals of diphenyl sulphoxide (0.67 g, 3.3 mmol, 62 %
}
} }
yield, ; 10.5 % overall yield relative to sulphur ; speci®c activity 31.9 mCi mol, chemical and radio-
}
chemical purities 99 %1 ), m.p. 69±70 ÊC and physical characteristics as previously reported (Hinsberg
1910, Barnard et al. 1949).
Animal dosing
Radioactive diphenyl sulphoxide (both U-14C- and 35S-) was suspended in an emulsion of corn oil
and water (3 1 v v) and administered by gavage (1.0 mmol kg body weight) to adult male rats (Wistar
}
}
}
strain, 250 g ; National Institute of Medical Research, London, UK) following an overnight fast. The
absolute dosage was determined gravimetrically.
Radioactive balance study
Following dosing with either [U-14C]-diphenyl sulphoxide or [35S]-diphenyl sulphoxide, animals
were housed in separate glass metabolism cages (`Metabowls’, Jencons Ltd, UK) for 4 days with free
access to food (`Lab Sure ’ rat pellets ; K. K. Greef Ltd, Croydon, UK) and water. Urine and faeces were
collected separately each day over solid carbon dioxide. During the [U-14C]-diphenyl sulphoxide
experiments, expired air was drawn through a series of Dreschel bottles containing ethanolamine in
methoxyethanol (2 1 v v) to trap 14CO and the solutions counted for radioactivity after 96 h as
}
}
#
described below. At the end of the study animals were killed by cervical dislocation and stored frozen
–
radioactivity.
(
20 ÊC). Cages were thoroughly cleansed with ethanol (50±100 ml) and the washings counted for
Tissue distribution and plasma levels
At known time intervals following the oral administration of [U-14C]-diphenyl sulphoxide, animals
were killed by cervical dislocation, exsanguinated, and the required organs and tissues removed and
–
weighed before being stored frozen ( 20 ÊC). In another series of studies, heparinized blood samples
were removed at various times from the tail veins of previously dosed animals, centrifuged and the
liberated plasma counted for radioactivity as described below.
Biliary secretion studies
Rats were anaesthetized with sodium pentobarbitone (50 mg kg body weight, i.p. ; `Sagatal’, Rhone
}
Poulenc, Dagenham, UK) and the common bile duct cannulated via a ventral mid-line incision just
caudal to the xiphoid cartilage. Bile was collected at regular intervals for up to 8 h; staggering the time

Disposition of diphenyl sulphoxide
717
interval between [U-14C]-diphenyl sulphoxide dosing and cannulation permitted a complete 0±24 h
pro®le to be obtained. The volume of bile produced was replaced with an equivalent volume of isotonic
saline via a tail vein cannula which also enabled augmentation of anaesthesia ensuring that all animals
remained unconscious throughout the study.
Quanti®cation of radioactivity
Aliquots (0.2±1.0 ml) of urine, bile, plasma, CO and SO trapping ¯uids, cage washings and bands
#
#
of silica gel removed from tlc plates, were added directly to vials containing scintillation ¯uid (10 ml,
`Ecoscint’; National Diagnostics Ltd, Atlanta, GA, USA) and counted by liquid scintillation
spectrometry using a Packard Tri-Carb 4640 scintillation counter (Canberra-Packard Instruments Ltd,
Pangbourne, UK) with external standards being used for quench correction.
Faecal samples were lyophilized, ground to a ®ne powder, and triplicate weighed samples (50±100 mg)
combusted in oxygen (Harvey Biological Material Oxidiser, Harvey Instrument Corp., NJ, USA). Any
14CO or 35SO being produced was trapped in an alkaline diphenylethylamine-containing scintillation
#
#
cocktail (15 ml) (Peterson et al. 1969) and counted as previously described.
Frozen carcasses were cut into small cubes with a bone-saw and dissolved in aqueous potassium
m
hydroxide (10 , 1 litre) at 18 ÊC for 7±10 days. The resultant liquid was homogenized, ®ltered through
glass wool and aliquots (1 ml) in scintillation vials decolourized with hydrogen peroxide (30 % v v ; 2 ml),
}
methanol (2 ml) being added to prevent eåervescence. After decolourization, the contents of the vials
were mixed thoroughly with distilled water (5 ml), followed by scintillation ¯uid (10 ml) and the vials
counted for radioactivity as described above. Stomach and intestines (both with contents) were digested
in aqueous potassium hydroxide as above whereas organs and tissues were homogenized in water.
Triplicate aliquots (1 ml) were then decolourized and counted for radioactivity as described above.
Chromatography
Tlc was performed on silica gel 60WF254s plates (0.2 mm thick, 203 20 cm, aluminium backed;
Merck, Darmstadt, Germany) and developed in toluene acetone (39 1, v v ; solvent 1) or toluene ethyl
}
}
}
}
acetate (1 1, v v ; solvent 2). Compounds were located under UV irradiation (254 nm) and the
}
}
naphthoresorcinol reagent used to visualize glucuronides (Elliott et al. 1959).
Gas chromatography-mass spectrometry (gc-ms) was carried out on a Hewlett Packard 5890 II series
gas chromatograph connected to a HP5971 mass selective detector operated in the electron impact mode
controlled by HPG 1034C software from the MS Chemstation (Hewlett Packard, Cheshire, UK). The
l
fused-silica capillary column (30 m3 0.25 mm i.d.) was coated (®lm thickness 0.25 m) with cross-linked
phenyl-methyl silicone (5 %) with a helium gas ¯ow of 1 ml min. The column oven was initially held at
70 ÊC for 2 min, then raised at 20 ÊC min until 290 ÊC was reached which was maintained for a further
}
}
2 min. The injection port was held at 250 ÊC. The gc-ms interface temperature, the ionization energy and
the ion source temperature of the mass spectrometer were 280 ÊC, 70eV and 185 ÊC, respectively.
Identi®cation and quanti®cation of metabolites
l
Aliquots (10±50 l) of neat radioactive urine were examined, either spotted or streaked, by tlc.
Reference compounds dissolved in control urine were co-chromatographed to provide provisional
identi®cation. Consecutive bands of silica gel (0.3 cm) were removed from the origin to solvent front of
dried developed tlc plates, added to vials containing scintillation ¯uid and counted as described above to
provide quanti®cation.
Pooled chloroform extracts (53 3 ml) of urine aliquots (1 ml) were dried (anhyd. CaCl ), concentrated
#
b
under nitrogen and examined by gc-ms. Additionally, urine (1 ml) was incubated with -glucuronidase
m
(1000 units, E. coli type IX ; Sigma Chemical Co., Dorset, UK) in phosphate buåer (1 ml; 0.1 , pH 6.8)
for 18 h at 37 ÊC. Control samples contained no enzyme. Both hydrolysed and control incubates were
lyophilized and the residues extracted with methanol (33 5 ml). Following centrifugation, the separated
methanol supernatant was reduced in volume under a dry nitrogen stream and examined by gc-ms. In
further studies, the lyophilized residues were vigorously shaken with methanol (2 ml) and kept sealed in
the dark for 24 h at 4 ÊC. Excess diazomethane in diethyl ether (generated from KOH on N-methyl-N-
nitroso-p-toluenesulphonamide, `Diazald ’) was then added until the solution remained yellow and the
mixture left for a further 24 h at room temperature. Following reduction to dryness under a nitrogen
stream, the residue was extracted with methanol (33 5 ml), centrifuged, and the separated supernatant
reduced in volume under nitrogen before examination by gc-ms.
Potential degradation of [35S]-diphenyl sulphoxide to inorganic sulphate was determined by a
decrease in radioactivity of a centrifuged urine sample to which ®ne powdered barium chloride had been
added until no further precipitation occurred. If a decrease in radioactivity was observed, the precipitate
itself was isolated, washed with water then methanol, and subjected to paper chromatography (Whatman
m
No 1 ; solvent isobutyric acid 1
sulphate (Amersham).
ammonia solution (5 :3 v v)) together with standard [35S]-sodium
}
}

718
S. C. Mitchell et al.
Spectrometric methods
UV spectra were obtained for compounds dissolved in ethanol (1 mg ml) in quartz cuvettes (1 cm)
}
using a Shimadzu MPS-200 UV spectrophotometer with Shimadzu PR-3 graphic printer and computer
facilities (V. A. Howe & Co., Ltd, London, UK). Infrared spectra were obtained via potassium bromide
discs or in CCl solution employing a Varian Fourier Transform I.R. (Varian Associates, Surrey, UK).
%
Electron impact mass spectrometry was undertaken using a Hewlett Packard 5971 series mass selective
detector attached to a capillary gas chromatograph as detailed above.
Results
Distribution and elimination studies
Virtually identical balance study pro®les were obtained with both positions of
radiolabel (table 1). Half of the administered radioactivity was recovered from the
faeces during the 4 days of the study, most being voided during the ®rst 2 days
(35±38 %) suggesting that a proportion of the dose may have passed through the gut
unabsorbed. However, 16.4‰ 1.1 % of the administered radioactivity traversed the
bile duct in the ®rst 0±24 h , with nearly half of this (7.5‰ 0.7 %) being excreted in
the ®rst 8 h ; the greatest ¯ow rate (1.35 % dose h) occurring 1±1.5 h after dosing.
}
This implies that enterohepatic cycling contributed to the retention of the
radioactivity in the animal. This is also seen within the urinary collections where
virtually the same amounts of radioactivity were voided during the ®rst and second
days ([U-14C]Ð19.3‰ 4.6 %, 16.8‰ 2.2 % ; [35S]Ð20.4‰ 8.2 %, 17.6‰ 4.8 %, re-
"
"
spectively ; not signi®cantly diåerent, 25 %
p
10 %, Student’s t-test), a total of
41±43 % being collected in the urine over 4 days of the study (table 1).
Plasma level data approximated a two-compartment oral (three-compartment)
model and displayed a peak concentration of 0.16 % dose ml (c ) at 40 min (t
)
}
max max
post-dosing. Assuming equal distribution and about 8 ml plasma in a 250 g rat
(Creskoå et al. 1942), this accounts for 1.28 % dose within the plasma at 40 min
post-dosing. The fraction of the dose which was absorbed was taken up quickly (t"ab
#
about 3 h) and rapidly distributed around the body (t"a 2 h) but then slowly
#
eliminated (t"b 22.5 h).
Results from tissue distribution studies were unremarkable. Small amounts of
#
the dose were found in the liver (c.4 % ; 0.4 % g) and kidney (c.1.4 % ; 0.7 % g)
}
}
during the ®rst 6 h, presumably re¯ecting excretion by these organs. These amounts
decreased slowly over the next 66 h . The majority of radioactivity was detected
within the gastrointestinal tract, appearing to move slowly from the stomach to
the intestines, although 3 % of the dose still remained within the stomach after
24 h (table 2). Between 5 and 11 % of the dose was found in the carcasses after 4 days.
!
No radioactivity was detected in expired air ( 0.1 % dose).
Metabolite identi®cation and quanti®cation
The failure to detect exhaled 14CO or any radiolabelled sulphate in the urine
#
suggested little or no degradation of the diphenyl sulphoxide molecule during its
passage through the rat. Excreta from the [35S]-diphenyl sulphoxide studies were
not examined further.
Analysis by tlc of 0±48 h urine samples collected from the [U-14C]-diphenyl
sulphoxide balance studies showed the presence of three radioactive areas. One co-
chromatographed with authentic diphenyl sulphoxide (R 0.17 solvent 1 ; R 0.43
f
f
solvent 2) accounting for 2.8‰ 1.1 % of the administered dose and another with

Disposition of diphenyl sulphoxide
719
Table 1. Excretion of radioactivity from the adult male Wistar rat dosed orally with radiolabelled
diphenyl sulphoxide (DPSO) (1.0 mmol kg body weight).
}
Percentage administered radioactivity
excreted
[U-14C]-DPSO
=
(n 12)
[35S]-DPSO
=
(n 4)
Urine
Day 1
19.3‰ 4.6
16.8‰ 2.2
3.8‰ 2.4
1.1‰ 0.5
41.0‰ 6.1
20.4‰ 8.2
17.6‰ 4.8
4.3‰ 2.1
0.8‰ 0.5
43.1‰ 8.3
Day 2
Day 3
Day 4
Total
Faeces
Days 1 and 2
Days 3 and 4
Total
37.8‰ 14.6
12.4‰ 6.6
50.2‰ 12.5
35.2‰ 12.2
14.4‰ 5.6
49.6‰ 10.1
Carcass
Cage washings
6.8‰ 2.1
0.5‰ 0.2
5.8‰ 3.1
0.6‰ 0.2
Total
98.5‰ 5.5
99.1‰ 5.1
Values quoted are mean‰ SD.
No radioactivity (less than 0.1 % dose) was detected in the expired air.
Table 2. Amounts of radioactivity remaining within organs of the male Wistar rat at various time
intervals following oral administration of [U-14C]-diphenyl sulphoxide (1.0 mmol kg body weight).
}
Time after
oral dose
(h)
Percentage of radioactive dose remaining in entire organ or structure
Stomach
Intestine
Liver
Kidney
Heart
Lung
1.0
3.0
6.0
72.0‰ 11.7
57.1‰ 5.0
28.2‰ 5.1
19.8‰ 5.9
16.1‰ 7.6
8.1‰ 4.8
3.2‰ 1.1
2.3‰ 0.4
2.0‰ 0.8
2.2‰ 0.5
1.2‰ 0.1
8.6‰ 2.6
29.3‰ 3.3
24.0‰ 1.8
32.9‰ 6.3
39.6‰ 2.0
26.5‰ 3.2
19.0‰ 6.2
12.4‰ 1.5
7.5‰ 1.0
4.3‰ 0.2
4.4‰ 0.8
3.5‰ 0.3
2.7‰ 0.2
2.6‰ 0.3
2.4‰ 0.1
1.7‰ 0.4
1.2‰ 0.2
1.2‰ 0.1
0.8‰ 0.1
1.0‰ 0.1
1.5‰ 0.2
1.4‰ 0.1
1.2‰ 0.2
1.0‰ 0.1
0.9‰ 0.3
0.8‰ 0.3
0.9‰ 0.2
0.8‰ 0.1
0.4‰ 0.2
0.5‰ 0.1
0.7‰ 0.1
0.3‰ 0.1 0.3‰ 0.1
0.2‰ 0.1 0.4‰ 0.2
0.2‰ 0.0 0.4‰ 0.1
0.2‰ 0.1 0.3‰ 0.2
0.2‰ 0.1 0.2‰ 0.0
0.1‰ 0.0 0.1‰ 0.0
0.1‰ 0.1 0.2‰ 0.1
0.2‰ 0.1 0.2‰ 0.0
0.2‰ 0.0 0.3‰ 0.1
0.1‰ 0.1 0.2‰ 0.0
0.2‰ 0.0 0.3‰ 0.0
9.0
12.0
18.0
24.0
36.0
48.0
60.0
72.0
5.6‰ 0.2
6.6‰ 1.2
=
Values are quoted as the mean‰ 1 SD (n 3).
Values obtained for the adrenals and spleen were always 0.1 % of the dose or below except for the
spleen at 1 and 3 h which gave values of 0.2 % dose.
authentic diphenyl sulphone (R 0.33 ; 0.54) accounting for 6.8‰ 2.4 % dose.
f
However, the majority of the radioactivity remained on the origin in both solvent
systems and gave a positive reaction with naphthoresorcinol indicative of glucuronic
acid conjugates although confusion with endogenous glucuronides was probable.
No evidence for diphenyl sulphide (R 0.63 ; 0.61) was obtained.
Chloroform extracts of 0±48 h urine examined by gc-ms con®rmed the presence
f
of diphenyl sulphoxide (R 10.5 min) (M1 , m z 202) and diphenyl sulphone (R
}
t
t
10.9 min) (M1 , m z 218) and the absence of the sulphide (R 8.8 min). In addition,
}
t
two peaks (R 12.8 and 13.0 min) were present which had virtually identical mass
t
spectra (M1 , m z 234) and could be interpreted as ring-hydroxylated diphenyl
}

720
S. C. Mitchell et al.
Figure 1. Electron impact mass spectra of ring-hydroxylated metabolite(s) of diphenyl sulphoxide
(oxidized to the sulphone) (1a) and these metabolite(s) following methylation with diazomethane (1b).
Interpretation of the fragmentation patterns is hampered by the formation of C-C and C-S bonds within
the spectrometer and the exclusion of C-S, C-O and S-O fragments (Bowie et al. 1966).
sulphone (or the dihydroxylated sulphoxide) (®gure 1). The areas of these latter
peaks nearly doubled after b-glucuronidase treatment, suggesting that 58 % of the
hydroxylated metabolites were present in the free form and 42 % as glucuronic acid
conjugates (presumably both on the tlc origin). Methylation of the hydrolysed urine
eåectively abolished the peaks at R 12.8 and 13.0 min and gave two new peaks at R
t
t
12.0 and 12.4 min.
Mass spectral examination of these new peaks provided fragment ions which
were 14 mass units higher (one methyl group) than previously observed (M1 , m z
}
248), permitting interpretation as ring mono-methoxylated diphenyl sulphone
(®gure 1). No further investigations as to the absolute position of the ring hydroxyl
groups were pursued. No examination of faecal or bile radioactivity was undertaken.

Disposition of diphenyl sulphoxide
721
Discussion
No overt toxicity was observed following oral diphenyl sulphoxide admini-
stration at 1.0 mmol(202 mg) kg body weight during this study. However, previous
}
studies have shown that the same dosage was fatal when administered i.p. to rat
(unpublished data from our laboratory) or s.c. to mouse (Hammett 1942). Diphenyl
sulphoxide appears to be poorly absorbed from the gastrointestinal tract with 50 %
of the dose eliminated via the faeces. However, biliary secretion (following
absorption) undoubtedly contributes to this faecal excretion and enterohepatic
recycling may prolong its retention within the animal. The lipophilic nature of
diphenyl sulphoxide may facilitate its entry into the lymphatic system and also its
retention within adipose cells (Barton et al. 1997), this latter phenomenon being
previously observed for p,p -dichlorodiphenyl sulphone which is concentrated in
´
fatty tissues (Mathews et al. 1996).
Although only urinary metabolites were investigated, no indication of molecular
degradation was observed and all metabolites contained the intact diphenyl
structure. The sulphoxide moiety was further oxidized to the sulphone but there was
no evidence for sulphoxide reduction. Previous studies employing perfused guinea-
pig liver have shown that diphenyl sulphoxide was further oxidized to the sulphone
presumably via cytochrome(s) P450 activity rather than FAD-monooxygenase
(Yoshihara and Tatsumi 1990). However, under conditions of hypoxia, and in the
presence of an electron donor (2-hydroxypyrimidine, benzaldehyde) for aldehyde
oxidase, diphenyl sulphide was produced (Yoshihara and Tatsumi 1990). Similar
enzymic conclusions have been drawn for the reduction of the sulphoxide within rat
and rabbit liver cystosols. However, diphenyl sulphoxide reduction via rat and
rabbit renal cystosols and via the cytosolic fraction of Escherichia coli was thought to
be mediated by a diåerent, thioredoxin-dependent, system (Lee and Renwick
1995a, b). Such interconversions are as expected, with the sulphoxide moiety being
intermediary in a redox sequence (Mitchell and Nickson 1993). In addition to
sulphone production, aromatic ring hydroxylation and the subsequent formation of
glucuronic acid conjugates appeared to be the major route of metabolism for
diphenyl sulphoxide. Previous studies have shown that p,p -dichlorodiphenyl
´
sulphone was excreted as a phenolic metabolite and its glucuronide both in the urine
and faeces of the orally dosed rat (Mathews et al. 1996), and presumably the majority
of radioactivity found within the faeces during the present studies may have been of
a similar nature.
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Disposition of diphenyl sulphoxide
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