Toxicology and Applied Pharmacology Volume 189, Issue
1, 15 May 2003, Pages 28-38
Experimental hepatic uroporphyria
induced by the diphenyl-ether herbicide fomesafen in male
DBA/2 mice
Jan
Krijt (a), Oskar Penák (a), Martin Vokurka (a),
Alena Chlumská (b) and Frantiek Fakan (b)
(a)
Institute of Pathophysiology, 1st Medical Faculty, Charles
University, 128 53, Prague, Czech Republic
(b) ikl’s Department of Pathology, Medical Faculty,
Charles University, Pilsen, Czech Republic
Hepatic
uroporphyria can be readily induced by a variety of treatments
in mice of the C57BL strains, whereas
DBA/2 mice are almost completely resistant.
However,
feeding of the protoporphyrinogen oxidase-inhibiting herbicide
fomesafen (0.25% in the diet for 18 weeks) induced hepatic
uroporphyria in male DBA/2N mice (liver porphyrin content
up to 150 nmol/g, control animals 1 nmol/g), whereas fomesafen-treated
male C57BL/6N mice displayed only a slight elevation of
liver porphyrins (~5 nmol/g).
The profile of accumulated hepatic porphyrins in fomesafen-treated
DBA/2N mice resembled the well-characterised uroporphyria
induced by polyhalogenated aromatic hydrocarbons, while
histological examination confirmed the presence of uroporphyria-specific
cytoplasmic inclusions in the hepatocytes. Uroporphyrinogen
decarboxylase activity decreased to about 30% of control
values in fomesafen-treated DBA/2N mice; microsomal methoxyresorufin
O-dealkylase activity was slightly reduced. The amount
of CYP1A1 and CYP1A2 mRNA, as determined by real-time
PCR, was not significantly changed; mRNA encoding the
housekeeping 5-aminolevulinic acid synthase was elevated
10-fold. Total liver iron was slightly increased.
A similar uroporphyria was induced by the herbicide formulation
Blazer, containing a structurally related herbicide acifluorfen,
when fed to DBA/2N mice at a dose corresponding to 0.25%
of acifluorfen in the diet. Since
DBA/2 mice are almost completely resistant to all well-characterised
porphyrogenic chemicals, the
results suggest the possible existence of a yet unknown
mechanism of uroporphyria induction, to which the DBA/2
mouse strain is more sensitive than the C57BL strain.
|
From Science Direct
Environmental Pollution, Volume 146, Issue 2, March 2007,
Pages 420-427
Lichens in a Changing Pollution Environment
Hemocyte-specific responses to the peroxidizing
herbicide fomesafen in the pond snail Lymnaea stagnalis (Gastropoda,
Pulmonata)
Jacqueline Russo (a), Luz Lefeuvre-Orfila
(b) and Laurent Lagadic (b)
(a) UMR 6553 Écobio CNRS Université de Rennes 1,
Campus de Beaulieu, F-35042 Rennes cedex 35042, France
(b) UMR 985 INRA-Agrocampus Écobiologie et Qualité
des Hydrosystèmes Continentaux, Équipe Écotoxicologie
et Qualité des Milieux aquatiques, 65 rue de Saint-Brieuc
CS 84215, F-35042 Rennes cedex 35042, France
Responses of circulating hemocytes were studied in Lymnaea stagnalis
exposed to 10, 30, 90, and 270 ?g/L fomesafen for 24 and 504 h.
Flow cytometry was used to quantify fomesafen-induced production
of reactive oxygen species (ROS), phagocytic activity on Escherichia
coli, and oxidative burst when hemocytes were challenged by E.
coli or phorbol 12-myristate-13-acetate (PMA). Lysosomal membrane
damage was assessed, using the neutral-red retention time (NRRT)
assay. Exposure to fomesafen for 24 h resulted
in increase in ROS levels and decreases in phagocytosis and the
oxidative burst in PMA-stimulated hemocytes. After 504
h, intracellular levels of ROS returned to normal, but phagocytosis
of E. coli was still inhibited and the associated oxidative burst
significantly reduced. After both durations of exposure, decreases
of NRRT indicated that lysosome membrane fragility increased with
previous termfomesafennext term concentration. Potential
implications for the health and survival of the snails and consequences
on populations are discussed.
Excerpt: The snails were individually exposed for 21 days to
the nominal fomesafen concentrations of 10, 30, 90 and 270 ?g/L.
Semi-static conditions of exposure were obtained by renewing the
contaminated water every three days. Acetone was used to solubilize
fomesafen. Solvent concentration in the exposure media was below
1 ?l/ml. Such levels do not alter the immunological responses
of L. stagnalis (Russo and Lagadic, 2004). Control snails were
maintained in either water contaminated with the carrier solvent,
or uncontaminated water, that was also renewed every three days.
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12206427&dopt=Abstract
Environ Toxicol
Chem 2002 Sep;21(9):1876-88
Nonylphenol
polyethoxylate adjuvant mitigates the reproductive toxicity of
fomesafen on the freshwater snail Lymnaea stagnalis in outdoor
experimental ponds.
Jumel A, Coutellec MA, Cravedi JP, Lagadic
L.
UMR 985 INRA-ENSAR Ecobiologie et Qualite des Hydrosystemes Continentaux,
Rennes, France.
The influence of nonylphenol polyethoxylates (NPEO), formulated
as the adjuvant Agral 90, on the effects of the diphenyl ether
herbicide fomesafen in the pond snail Lymnaea stagnalis was investigated,
with particular attention to the reproductive performances and
underlying energetic and hormonal processes. Separate short-term
exposures to low concentrations of fomesafen and fomesafen-Agral
mixture were performed in the laboratory. Outdoor experimental
ponds (mesocosms) were used for long-term exposures to higher
chemical concentrations. At the concentrations used in the studies,
NPEO were known as nontoxic in L stagnalis. Fomesafen was mixed
with the adjuvant in the 3:7 ratio recommended for agricultural
uses (nominal herbicide concentrations of 22 and 40 microg/L in
laboratory and mesocosm, respectively).
In mesocosms, multiple application of fomesafen, leading to maximal
herbicide concentrations of 60.33 +/- 2.68 microg/L in water,
resulted in reduced number of egg masses and altered glycogen
metabolism in contaminated snails. These changes, as well as affected
steroid-like levels in fomesafen-exposed snails, support the hypothesis
of impaired neuroendocrine functions. When Agral 90 was
added to the herbicide, results obtained in mesocosms showed that
the adjuvant softened the impact of fomesafen. In mesocosms treated
with the fomesafen-Agral mixture, significantly lower herbicide
levels were found in the water (30.33 +/- 14.91 microg/L at the
end of the contamination period). Consequently, internal exposure
of the snails to fomesafen was reduced when the herbicide was
mixed with the adjuvant. Mitigation of the effects of fomesafen
by the adjuvant may therefore result from nonionic surfactant
activity of NPEO that prevented fomesafen from reaching the snails.
PMID: 12206427 [PubMed - in process]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12216501&dopt=Abstract
Acta Cient
Venez 2002;53(1):60-5
[Participation
of dexamethasone and E and C vitamins in the modulation of the
hepatotoxic effect induced by fomesafen and 2,4-D amino herbicides,
in rats ]
[Article in Spanish]
Orfila L, Mendoza S, Rodriguez J, Arvelo
F.
Instituto de Investigaciones Farmaceuticas, Unidad de Cultivo
Celular-Toxicologia, Facultad de Farmacia Universidad Central
de Venezuela, Caracas-Venezuela.
The fomesafen and 2,4-D amine herbicide induce cytotoxic effects
at hepatic level in rats, such as: hepatomegaly, hyperplasia and
increase in the enzymes activity which participate in the processes
of peroxisomal beta-oxidation of fatty acids. In this work, the
effect of vitamin E and C was evaluated, as well as, the dexamethasone
in the modulation of these hepatotoxic effects. Sprague-Dawley
rats were treated with the herbicides and with the agents to be
evaluated. The different treatments were given during 15 days
orally route. The herbicides combined with the dexamethasone and
antioxidant agents were administrated only and simultaneously
with the herbicides. Once concluded the different treatment, the
rats were weighed and sacrificed. It was evaluated the liver size
and liver fragments were obtained to determine the enzymatic activity
of Fatty Acyl CoA-oxidase (FACO) and cellular number. The results
showed that the hepatomegaly induced by fomesafen was inhibited
by the vitamins and by the dexamethasone, while any effect was
not observed in the group of rats treated with 2,4-D amine. None
of the agents modulated the FACO activity induced by herbicides
in treated rats. However, the dexamethasone showed a protective
effect in the hyperplasia induced by two herbicides. The hepatotoxic
effects induced by the herbicides responded to a different mechanism
due to the differences of the effects observed at the antioxidant
agents. On the other hand, the inhibition of the cellular proliferation
by the dexamethasone does not keep relation with the responsible
mechanisms of inducing the oxidant stress into FACO activity.
Under experimental conditions of this study, the use of these
agents does not guarantee protection against the hepatotoxic effects
induced by the herbicides.
PMID: 12216501 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10372757&dopt=Abstract
Hum Exp Toxicol
1999 May;18(5):338-44
Liver
preneoplastic changes in mice treated with the herbicide fomesafen.
Krijt J, Stranska P, Sanitrak J, Chlumska
A, Fakan F.
Institute of Pathophysiology, First Faculty of Medicine, Charles
University, Prague, Czech Republic.
1. Effect of the diphenyl ether herbicide fomesafen on liver preneoplastic
changes and porphyrin biosynthesis was examined in male C57BL/6J
mice (0.23% in the diet for 14 months) and ICR mice (0.3% in the
diet for 50 weeks). Fomesafen treatment resulted in preneoplastic
changes (liver nodules and foci of altered hepatocytes) in both
strains, uroporphyria developed only in ICR mice.
2. Iron pretreatment (600 mg/kg as a single dose) accelerated
the development of fomesafen-induced preneoplastic changes in
both mouse strains. The number of foci containing altered hepatocytes,
as well as the number and size of liver nodules, were increased
in iron-pretreated animals.
3. A single injection of iron induced marked uroporphyria in C57BL/6J
mice after 14 months (liver porphyrin content 102 nmol/g). This
uroporphyria was further potentiated by fomesafen administration
(208 nmol/g).
4. In ICR mice, liver histology was apparently normal after a
3 month recovery from fomesafen treatment (0.32% for 9 months).
Liver porphyrin content (260 nmol/g) started to decrease immediately
after fomesafen withdrawal, but was still significantly elevated
after 3 months (5 nmol/g), as compared to controls (1 nmol/g).
5. It is concluded that the toxicological
evaluation of fomesafen should focus on liver porphyrin biosynthesis.
PMID: 10372757 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9624829&dopt=Abstract
Cesk Patol
1998 Apr;34(2):67-71
[Morphologic
findings in liver tissue in mice after long-term administration
of the herbicide fomesafan]
[Article in Czech]
Chlumska A, Fakan F, Krijt J.
II. patologicko-anatomicky ustav 1. LF UK a VFN, Praha.
Administration of herbicide fomesafen and of fomesafen combined
with one dose of iron to 44 mice during 3 to 14 months caused
hyperplastic and preneoplastic changes in the liver tissue which
had been described in experimental carcinogenesis* small groups
of altered hepatocytes storing glycogen or lipids and foci of
small basophilic liver cells occurred as early as after 3 months.
Altered hepatocytes were found more frequently in mice getting
fomesafen and iron. Later nodular hyperplasia of liver cells developed
with nodes 3-20 mm in diameter which mostly consisted of altered
hepatocytes with plenty of glycogen. After 12 and 14 month-lasting
administration of fomesafen and fomesafen with iron, the hepatocellular
carcinoma was proved in 5 mice. In 4 mice, the preneoplastic changes
in liver tissue were accompanied by micronodular hyperplasia of
liver cells which did not participate on the development of big
nodes and hepatocellular carcinoma.
PMID: 9624829 [PubMed - indexed for MEDLINE]
From Toxline at Toxnet
TOXICOLOGY AND APPLIED PHARMACOLOGY; 146 (1). 1997.
170-171.
LETTERS TO THE EDITOR AND REPLY
KRIJT J, VOKURKA M, RICHERT L
Abstract: BIOSIS COPYRIGHT: BIOL ABS. RRM LETTER HUMAN TOXICOLOGY
FOMESAFEN HERBICIDE FLUAZIFOP OXADIAZON HEPATOCARCINOGEN TUMOR
BIOLOGY DIGESTIVE SYSTEM HEPATOCELLULAR CARCINOMA PORPHYRIN NEOPLASTIC
DISEASE DIGESTIVE SYSTEM DISEASE
From Toxline at Toxnet
TOXICOLOGY IN VITRO; 11 (1-2). 1997.
99-105.
Quantitative structure-activity relationship
(QSAR) analysis for a series of rodent peroxisome proliferators:
Interaction with the mouse liver peroxisome proliferator-activated
receptor alpha (mPPARalpha).
LEWIS D FV, LAKE BG
Sch. Biol. Sci., Univ. Surrey, Guildford, Surrey GU2 5XH, UK.
BIOSIS COPYRIGHT: BIOL ABS. The results of quantitative structure-activity
relationship (QSAR) analysis on a structurally diverse group of
peroxisome proliferators are reported. The relative potencies
of 11 peroxisome proliferators (with respect to clofibric acid)
for induction of palmitoyl-CoA oxidation in rat hepatocyte cultures
appear to be determined by a combination of lipophilicity (logP
descriptor) and calculated binding affinity (logK) to a model
of the mouse liver peroxisome proliferator-activated receptor
alpha (mPPARalpha) ligand-binding domain. It is possible that
desolvation of the putative binding site and ligand ionization
may also play a role in activation of the mPPARalpha.
CAS Registry Numbers:
88107-10-2
72178-02-0 - Fomesafen
50892-23-4
21340-68-1
4376-20-9
3771-19-5
882-09-7
76-03-9
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8993577&dopt=Abstract
Ann N Y Acad
Sci 1996 Dec 27;804:628-35
Peroxisome
proliferators: species differences in response of primary hepatocyte
cultures.
Elcombe CR, Bell DR, Elias E, Hasmall SC,
Plant NJ.
Zeneca Central Toxicology Laboratory,
Macclesfield, Cheshire, U.K.
PMID: 8993577 [PubMed - indexed for MEDLINE]
From Toxline at Toxnet
Source: REDDY, J. K., ET AL. (ED.). ANNALS OF THE NEW YORK ACADEMY
OF SCIENCES, VOL. 804. PEROXISOMES: BIOLOGY AND ROLE IN TOXICOLOGY
AND DISEASE; INTERNATIONAL SYMPOSIUM, ASPEN, COLORADO, USA, JUNE
28-JULY 2, 1995. XV+801P. NEW YORK ACADEMY OF SCIENCES: NEW YORK,
NEW YORK, USA. ISBN 0-89766-968-1(PAPER); ISBN 0-89766-967-3(CLOTH).;
804 (0). 1996. 628-635.
PEROXISOME PROLIFERATORS SPECIES DIFFERENCES
IN RESPONSE OF PRIMARY HEPATOCYTE CULTURES
ELCOMBE CR, BELL DR, ELIAS E, HASMALL SC, PLANT NJ
Abstract: BIOSIS COPYRIGHT: BIOL ABS. RRM BOOK CHAPTER MEETING
PAPER RAT MOUSE GUINEA-PIG MONKEY HUMAN PEROXISOME PROLIFERATORS
CARCINOGENS SPECIES DIFFERENCES PEROXISOME PROLIFERATION CULTURED
PRIMARY HEPATOCYTES HEPATOCELLULAR GROWTH RESPONSE CELL BIOLOGY
DIGESTIVE SYSTEM TOXICOLOGY DIGESTIVE SYSTEM
CAS Registry Numbers:
72178-02-0 (Fomesafen)
40321-98-0
149-57-5
76-03-9
Toxicology Letters, Volume 78, Supplement 1, August 1995,
Page 77
Effect of the peroxisome proliferating
diphenyl etther herbicide fomesafen on liver porphyrin biosynthesis
and neoplastic transformation—synergism with iron pretreatment
P. Stránská (1), A. Chlumská
(2) , M. Vokurka (1), P. Maruna (1), J. Sanitrik (1), V. Janousek
(1) and J. Krijt (1)
(a) Medical Faculty, Charles University, Prague
(b) Second Department of Pathological Anatomy First Medical Faculty,
Charles University, Prague
Note from FAN: We copied the following
abstract from a poorly legible abstract sheet. Any mistakes in
typing are ours. - EC.
Although the diphenyl ether herbicides are in widespread use,
their mode of action was elucidated only recently, In addition
to their affect of porphyrin metabolism, some of the diphenyl
ether herbicides cause hepatocellular carcinoma in rodents. The
aim of the presented study was to evaluate the porphyrogenic effects
of fomesafen in a long term experiment. 12 male ICR mice were
fed 0.3% of the herbicide for 12 months. Another group of 12 mice
was pretreated with iron (600 mg/kg) and fed either fomesafen
diet, or control diet. After six months of treatment, the liver
porphyrin content was 69.9± ug/g in the fomesafen group
and :52.2± 52.6 in the fomesafen plus iron group. No increase
in porphyrin content was evident in iron pretreated mice. Liver
histology showed necrotic foci in fomesafen treated animals. Peroxisomal
B-oxidation was increased in both fomesafen treated animals.
After 12 months of treatment, liver porphyrin content was 56 ±
18 ug/g in the fomesafen group and 107 ± 36 in the fomesafen
plus iron group. No increase in porphyrin content was evident
in iron pretreated mice. Liver histology showed necrotic foci
in fomesafen treated animals. Peroxisomal B-oxidation was increased
in both fomesafen fed group. The porphyrin content of iron pretreated
mice was slighly increased to about 250% of control values. On
macroscopic examination, livers from the fomesafe nplus iron group
showed multiple liver nodules. Histological examination revealed
mainly adenomas and one hepatocellular carcinoma. No nodules were
observed in mice fed fomesafen only. The
results indicate that iron significantly increased the porphyrogenic
activity of fomesafen, as well as tyhe tumoroganic activity. These
results closely resemble the effects obtained with other porphyrogenic
heptacarcinogens, like HCB, TCDD or PCBs. Therefore, the changes
inporphyrin metabolism could be an additional factor in fomesafen-induced
neoplasia.
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7855041&dopt=Abstract
Pharm Res
1994 Oct;11(10):1396-400
Vehicle
effects on in vitro percutaneous absorption through rat and human
skin.
Hilton J, Woollen BH, Scott RC, Auton TR,
Trebilcock KL, Wilks MF.
Zeneca Central Toxicology Laboratory,
Macclesfield, Cheshire, England.
We studied the effects of three vehicles (propylene glycol, octanol
and ethyl decanoate) with differing polarity on the in vitro percutaneous
absorption of three chemicals (fluazifop-butyl, dimethyl phthalate
and fomesafen sodium salt) with a range of physico-chemical properties.
Absorption rate measurements were made from high vehicle volume
(200 microliters/cm2) and low vehicle volume (< 10 microliters/cm2)
applications. For the lipophilic fluazifop-butyl absorption rate
was highest from the more polar vehicle propylene glycol, but
this effect was only significant under high-volume conditions.
There was a variable vehicle effect on absorption of the intermediate
chemical dimethyl phthalate. The largest vehicle effect was seen
for the more hydrophilic fomesafen sodium salt where absorption
was fastest from the least polar vehicle ethyl decanoate. These
results support the hypothesis that the absorption process can
in part be predicted from a knowledge of solute solubility. Vehicle
effects were greater from high volume applications than from those
more comparable to occupational exposure conditions.
PMID: 7855041 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8045477&dopt=Abstract
Food Chem
Toxicol 1994 Jul;32(7):641-50
Effect
of the protoporphyrinogen oxidase-inhibiting herbicide fomesafen
on liver uroporphyrin and heptacarboxylic porphyrin in two mouse
strains.
Krijt J, Vokurka M, Sanitrak J, Janousek
V, van Holsteijn I, Blaauboer BJ.
Department of Pathological Physiology, First Medical Faculty,
Charles University, Prague, Czech Republic.
The effect of the protoporphyrinogen oxidase-inhibiting herbicide
fomesafen on liver porphyrin accumulation was studied in long-term
high-dose experiments. Fomesafen caused liver accumulation of
uroporphyrin and heptacarboxylic porphyrin when fed at 0.25% in
the diet to male ICR mice for 5 months (fomesafen-treated mice:
52 nmol uroporphyrin, 21 nmol heptacarboxylic porphyrin/g liver;
control mice: traces of uroporphyrin, heptacarboxylic porphyrin
not detected). Uroporphyrinogen decarboxylase activity was depressed
to about 25% of control values. Iron treatment accelerated the
development of this porphyria cutanea tarda-like experimental
porphyria both in ICR and C57B1/6J mice. In contrast to other
uroporphyrinogen decarboxylase inhibitors, fomesafen treatment
did not increase the cytochrome P450IA-related activities and
the amount of P450IA2 protein was shown to be significantly decreased
by Western immunoblotting. Thus, fomesafen is a unique chemical
that inhibits both the oxidation of protoporphyrinogen as well
as the conversion of uroporphyrinogen to coproporphyrinogen. However,
the accumulation of highly carboxylated porphyrins is evident
only after prolonged treatment with high doses of the herbicide.
PMID: 8045477
[PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7958570&dopt=Abstract
Fundam Appl
Toxicol 1994 Jul;23(1):93-100
Effect
of dosing vehicle on the dermal absorption of fluazifop-butyl
and fomesafen in rats in vivo.
Rawlings JM, Hilton J, Trebilcock KL, Woollen
BH, Wilks MF.
Zeneca Central Toxicology Laboratory,
Alderley Park, Macclesfield, Cheshire, England.
One important factor which may influence the extent and rate of
percutaneous absorption is the dosing vehicle. The purpose of
the experiments described was to compare the effect of dosing
vehicles of different polarities on the absorption of two herbicides
across rat skin in vivo. Rats were dosed dermally with either
fluazifop-butyl (logP(oct) 4.5) or fomesafen sodium salt (logP(oct)
-1.2) in propylene glycol (PG), octanol (OCT), or ethyl decanoate
(ED), and the amount of radioactivity excreted in urine was determined.
Absorption rates were estimated from the urinary excretion data
and from blood kinetic data derived from intravenously dosed rats.
For fluazifop-butyl the average rate of absorption (x10(-2) micrograms/hr-1
+/- SE) was not greatly influenced by the dosing vehicle (OCT,
2.94 +/- 0.08; ED, 3.66 +/- 0.10; PG, 3.95 +/- 0.32) despite relatively
large differences in solubility (PG, 38 mg/ml; OCT, and ED, >
600 mg/ml). These results were consistent with the finding that
there was at most only a twofold difference in the epidermal membrane:vehicle
partition coefficients (km). In contrast, the absorption rate
of fomesafen from PG (1.98 +/- 0.04) was approximately half that
of ED (3.98 +/- 0.06) and OCT (4.49 +/- 0.08) for the first 30
hr after application and was in keeping with solubility data (PG,
638 mg/ml; OCT, 12 mg/ml; ED, < 10 mg/ml). At later time points
the absorption of fomesafen from PG increased; this is discussed
in relation to the penetration-enhancing properties of PG.(ABSTRACT
TRUNCATED AT 250 WORDS)
PMID: 7958570 [PubMed - indexed for MEDLINE]
From Toxline at Toxnet
Rev. Fac. Farm. Univ. Cent. Venez.; VOL 57 ISS 1 1994,
P6-11, (REF )
Cytotoxic activity of the herbicide fomesafen
in rat hepatocytes treated in vitro
Orfila L, Salazar-Bookaman M
Unidad de Cultivo Celular, Fac. de Farmacia, Univ. Central de
Venezuela, Apdo. 40109, Caracas 1040-A, Venezuela
No abstract available
Keywords:
Fomesafen
effects
cytotoxicity
Herbicides
cytotoxic effects
CAS Registry Number:
72178-02-0 - Fomesafen
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8517781&dopt=Abstract
Arch Toxicol
1993;67(4):255-61
Effect
of diphenyl ether herbicides and oxadiazon on porphyrin biosynthesis
in mouse liver, rat primary hepatocyte culture and HepG2 cells.
Krijt J, van Holsteijn I, Hassing I, Vokurka
M, Blaauboer BJ.
Research Institute of Toxicology, University of Utrecht, The Netherlands.
The effects of the herbicides fomesafen, oxyfluorfen, oxadiazon
and fluazifop-butyl on porphyrin accumulation in mouse liver,
rat primary hepatocyte culture and HepG2 cells were investigated.
Ten days of herbicide feeding (0.25% in the diet) increased the
liver porphyrins in male C57B1/6J mice from 1.4 +/- 0.6 to 4.8
+/- 2.1 (fomesafen) 16.9 +2- 2.9 (oxyfluorfen) and 25.9 +/- 3.1
(oxadiazon) nmol/g wet weight, respectively. Fluazifop-butyl had
no effect on liver porphyrin metabolism.
Fomesafen, oxyfluorfen and oxadiazon increased the cellular porphyrin
content of rat hepatocytes after 24 h of incubation (control,
3.2 pmol/mg protein, fomesafen, oxyfluorfen and oxadiazon at 0.125
mM concentration 51.5, 54.3 and 44.0 pmol/mg protein, respectively).
The porphyrin content of HepG2 cells increased from 1.6 to 18.2,
10.6 and 9.2 pmol/mg protein after 24 h incubation with the three
herbicides. Fluazifop-butyl increased hepatic cytochrome P450
levels and ethoxy- and pentoxyresorufin O-dealkylase (EROD and
PROD) activity, oxyfluorfen increased PROD activity. Peroxisomal
palmitoyl CoA oxidation increased after fomesafen and fluazifop
treatment to about 500% of control values both in mouse liver
and rat hepatocytes. Both rat hepatocytes and HepG2 cells can
be used as a test system for the porphyrogenic potential of photobleaching
herbicides.
PMID: 8517781 [PubMed - indexed for MEDLINE]
•• Abstract
from Toxline at Toxnet on this paper:
Porphyrin accumulation in mouse liver, rat primary hepatocyte
culture and HepG2 cells was investigated after exposure to
fomesafen (72178-02-0), oxyfluorfen (42874-03-3), oxadiazon,
and fluazifopbutyl (69806-50-4) (fluazifop). Male C57Bl/6J-mice
were fed a diet containing 0.25% herbicide, sacrificed after 10
days, and the livers prepared for culture. Hepatocytes were isolated
from Wistar-rats and treated with herbicide after being in culture
for 24 hours. Fomesafen, oxyfluorfen and
oxadiazon significantly increased the porphyrin content of mouse
liver, as well as the porphyrin content of rat hepatocytes and
HepG2 cells in culture. Fluazifop did not have any effect
on porphyrin accumulation. The extent of in-vitro porphyrin accumulation
induced by fomesafen, oxyfluorfen and oxadiazon in the rat primary
hepatocyte culture was roughly similar. Fomesafen
and fluazifop caused a significant increase in the activity of
peroxisomal palmitoyl-coenzyme-A oxidation both in rat primary
hepatocyte culture and in mouse liver. Hepatic cytochrome
levels were increased by fluazifop and there were also increases
in ethoxyresorufin-O-dealkylase and pentoxyresorufin-O-dealkylase
activities. The authors conclude that both
the rat hepatocytes and HepG2 cells can be used to study porphyrogenic
activity of protoporphyrinogen-oxidase inhibiting herbicides.
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2689246&dopt=Abstract
Food Addit
Contam 1989;6 Suppl 1:S57-65
Mechanistic
studies: their role in the toxicological evaluation of pesticides.
Smith LL, Elcombe CR.
Central Toxicology Laboratory, Imperial Chemical Industries plc,
Cheshire, UK.
To date, studies on the mechanism of toxicity of pesticides are
not yet an integral part of the toxicological evaluation process.
However, in recent years mechanistic studies have played an increasing
role in the assessment of toxicological hazards to man, and in
this paper we have described two examples where an understanding
of mechanism has contributed positively to risk assessment or
has provided a surer scientific basis for the judgement of whether
a potential hazard will be expressed in man. In the first example,
an evaluation of the scientific literature leads to the conclusion
that hepatic peroxisome proliferation in rats and mice is directly,
or indirectly, related to the development of hepatocellular tumours.
A wide range of non-mutagenic chemicals elicit peroxisome proliferation
in mouse and rat liver, but not the guinea pig or marmoset liver.
Using one of the diphenyl ether herbicides, fomesafen, we have
shown that isolated hepatocytes from mice and rats, but not those
from guinea pigs, marmosets and significantly man, undergo peroxisome
proliferation. Therefore, it seems reasonable to conclude that
although fomesafen causes peroxisome-related tumours in the mouse,
man is neither susceptible nor sensitive to this mechanism. Consequently,
we can conclude that fomesafen will not cause liver tumours in
humans exposed to this herbicide. The herbicide paraquat, although
safe in normal agricultural use, has been responsible for numerous
human fatalities, almost exclusively as a result of the intentional
ingestion of the concentrated commercial product.(ABSTRACT TRUNCATED
AT 250 WORDS)
Publication Types:
PMID: 2689246
[PubMed - indexed for MEDLINE]
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