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TERATOLOGY 54150-156 (1996)
All-Trans-Retinoyl-P-Glucuronide
Is a Potent
Teratogen in the Mouse Because of Extensive
Metabolism to All-Trans-RetinoicAcid
H. NAU, M.M.A. ELMAZAR, R. ROHL, R. THIEL, AND J.O. SASS
Znstitut fur Toxikologie und Embryopharmakologie, Fachbereich Humunmedizin, Freie Universitiit Berlin, 0-14195
Berlin, Germany (H.N., R.R., R.T.); King Suud University, College of Pharmacy, Riyudh 1145,Saudi Arabia
M.M.A.E.); Universitatsklinik fur Kinder- und Jugendheilkunde, A-9020 Innsbruck, Austria (J.O.S.); Department of
Food Toxicology, Veterinary Medical University of Hannover, 0-30173 Hannover, Germany (H.N.)
Al I - trans- retinoyl- p - D- g IucuABSTRACT
ronide (all-trans-RAG) is a water-soluble derivative
of all-frans-retinoic acid (all-frans-RA) and has
been characterized as an endogenous metabolite
of vitamin A in rat bile and kidney. All-frans-RAG
was previously demonstrated to be a maior metabolite after application of all-trans-RA in several
species (mouse, rat, rabbit, monkey); all-transRAG was described in these experiments to exhibit
a very low placental transfer to the embryo. Because retinoid-like activity has been found after
application of all-frans-RAG in vivo as well as in
several in vitro systems, and because of its low
placental transfer, this glycoconjugate appeared
to be an interesting retinoid with possible therapeutic activity, but reduced teratogenicity. Here we
investigated the teratogenic activity of all-transRAG in comparison to all-frans-RA in mice, and
performed accompanying pharmacokinetic studies. Surprisingly,all-frans-RAGwas moreteratogenic than equimolar doses of all-frans-RA following
subcutaneous application on day 11 of gestation in
the mouse (20 prnol/kg body weight). Pharmacokinetic studies revealed that all-trans-RAG was extensively hydrolyzed to all-trans-RA and that the
plasma area under the concentration-time curve
(AUC) of all-trans-RA following all-trans-RAG application exceeded the plasma AUC value of allfrans-RA following application of all-frans-RA. Extensive hydrolysis of all-trans-RAG was also
observed after intravenous application of this glycoconjugate. Transfer of all-frans-RAG to the embryo was low, but transfer was high to maternal
organs such as the liver and kidney. These in vivo
studies suggest that all-trans-RAG serves as a precursor of all-trans-RA by the intravenous and subcutaneous routes, and application of all-transRAG results in high and teratogenic in vivo
exposure to all-frans-RA. o 1996 WiIey-Liss, Inc.
tabolite in rat bile, small intestine, and liver (Dunagin
et al., '65; Zile e t al., '82; McCormick et al., '83). This
glycoconjugate of all-truns-retinoic acid (all-truns-RA)
was also purported to occur as a n endogenous component in human plasma (Barua and Olson, '86). Subsequently, all-truns-RAG was identified as a major metabolite after application of pharmacologic or toxic
doses of retinol and all-truns-RA to mice (Creech Kraft
et al., '91a), rats (Collins e t al., '95), rabbits (Tzimas et
al., '94a), and monkeys (Eckhoff et al., '90, '91; Creech
Kraft et al., '91b; for reviews see Nau, '93, '94). p-Glucuronides of retinol, 13-cis-retinoic acid and 9-cis-retinoic acid (Eckhoff et al., '91; Creech &aft et al., '91a,b;
Sass e t al., '94, '95; Tzimas e t al., '94b), were also identified and quantitated following administration of the
respective aglycones.
All-truns-RAG attracted attention because it exerted
retinoid-like biological activity in a variety of in vitro
systems such a s the cultured human promyelocytic leukemia cell line HL-60 (Zile et al., '87; Janick-Buckner
et al., '91) and mammary gland in organ culture
(Mehta et al., '91). In these systems, all-truns-RAG
acted potently in regard to inhibition of proliferation
and induction of differentiation. Administration of alltrans-RAG promoted the growth of vitamin A deficient
rats. However, from those experiments it was not clear
if all-truns-RAG acted directly or following hydrolysis
to all-truns-RA. When analytical measurements were
performed it became clear that a considerable portion
of all-truns-RAG had been hydrolyzed in vitro and the
resulting all-truns-RA was found in the medium as
well as in the cultured tissue (Tzimas et al., '94c; Ruhl
et al., '94; Foerster et al., '96). Considerable hydrolysis
was also observed after intraperitoneal (i.p.) application of a tracer dose of 3H-all-truns-RAG in the rat
Received April 22, 1996; accepted July 29, 1996.
All-truns-retinoyl-p-D-glucuronide(all-truns-RAG)
was first identified as an endogenous vitamin A me-
0 1996 WILEY-LISS, INC.
Address reprint requests to Dr. Heinz Nau, Dept. of Food Toxicology,
Veterinary Medical University of Hannover, Biinteweg 15/115,
D-30173 Hannover, Germany.
ALL-!l"S-RETINOYL-P-GLUCURONIDE
(Barua and Olson, '89). Retinoid glucuronides do not
interact with cytosolic retinoid binding proteins
(Mehta et al., '92) or retinoid receptors (Sani et al., '92),
which could be taken as an argument against a direct
action of these glycoconjugates.
Also further retinoid-glycoconjugates were shown to
exert biological activity including all-truns-retinoyl-pglucose (Barua and Olson, '91, '92), all-truns-retinyl-pglucuronide (Barua and Olson, '871, all-truns-retinyl-pglucose (Barua and Olson, ,921, the p-glucuronide of
N-(4-hydroxypenyl)-retinamide(Bhatnagar et al., '91)
and derivatives (Doepner et al., '92; Kaleagasioglu et
al., '93; Panigot et al., '94; Robarge et al., '94).
Teratogenicity is an extremely serious side effect of
essentially all active retinoids synthesized and tested
up to now (Kochhar, 1967; for a review, cf. Nau et al.,
1994). It is likely that the teratogenic activity is mediated by nuclear retinoid receptors which may also be
crucially involved in the pharmacological effect of
retinoid drugs in dermatology or oncology (Chambon,
'93). A number of retinoid receptors have been shown to
be expressed in embryonic tissue in a very specific spatial-temporal fashion, and it appears to be extremely
difficult to develop novel retinoids which interact with
the retinoid receptors in the desired target tissue of
pharmacologic action, but do not interact with embryonic receptors.
We have been following another lead to retinoids
with low teratogenic activity: retinoids exhibiting limited transfer to the embryo. We have demonstrated
that all-truns-RAG, produced as metabolite of alltruns-RA, was transferred to the embryo to a very limited degree, and only a few percent of maternal plasma
all-truns-RAG concentrations were found in the embryo of the mouse (Creech Kraft et al., '91a), rat (Collins et al., '94, '951, rabbit (Tzimas et al., '94a; Collins et
al., '95), and monkey (Hummler et al., '94). Very low
embryo/maternal plasma concentration ratios were
also found for the p-glucuronides of 13-cis-retinoic acid
(Creech-Kraft et al., '91a; Tzimas et al., '94a), 9 4 s retinoic acid (Sass et al., '94; Tzimas et al., '94b) and
retinol (Collins et al., '94).
The low placental transfer of retinoid-p-glucuronides, together with the biological activity of these
glycoconjugates in vitro discussed above, prompted us
to study the teratogenic activity of all-trans-RAG in
vivo in mice. Gestational day (GD) 11 represents a
suitable stage for treatment of mice, in order to assess
teratogenic potencies of retinoids by morphologic evaluation of near-term fetuses; resorption, growth retardation, cleft palate and limb reduction defects are reliable end-points (Kochhar and Satre, '93). Parallel
pharmacokinetic studies were performed for the rational interpretation of the results from our teratology
study. Area under the concentration-time curve (AUC)
values were used as exposure parameters because they
have been previously shown to correlate well with teratogenic activity of retinoids (Nau, '90, '94).
151
MATERIALS AND METHODS
Laboratory precautions
All work with retinoids was performed under dim
amber light to avoid photodegradation. Retinoids and
their solutions as well as biological samples for retinoid
analysis were stored at -20°C.
Chemicals
Retinoic acid isomers were provided by Hoffmann-La
Roche (Basel, Switzerland). All-truns-RAGwas synthesized following a modification of the method of Barua
and Olson ('87, '89) which has been reported recently
(Foerster et al., '96). All chemicals for the synthesis
were generously provided by BASF AG (Ludwigshafen,
Germany). Organic solvents of highest purity and trifluoracetic acid were purchased from Merck (Darmstadt, Germany). Water was purified with a Milli-Q
water purification system (Millipore, Eschborn, Germany).
Animals
NMRI mice (Han: NMRI; Zentralinstitut fiir Versuchstierzucht, Hannover, Germany, or Harlan-Winkelmann, Borchen, Germany) were kept under specific
pathogen free (spf) conditions and a 12-hr standard
light-dark cycle. They received a standard pellet diet
(Altromin 1324; Altromin, Lage, Germany) and tap
water ad libitum. The animals were mated during 2-hr
period in the morning. The following 24 hr interval
was considered gestational day (GD)0.
Teratologic study
On GD 11,mice received a single subcutaneous (s.c.)
dose of 20 pmol all-truns-RAG or all-truns-RAkg body
weight (b.wt.). The dosing volume was 1 mlkg; the
vehicle was dimethyl sulfoxide (DMSO). A control
group was administered the pure solvent. On GD 18,
the dams were killed by cervical dislocation. Implantation sites, resorptions, and live fetuses were counted.
Live fetuses were weighed individually and examined
for external malformations. The fetuses were then preserved in 5% formalin solution until examined for internal malformations. Skeletal abnormalities were examined after staining with alizarin red S. Results are
compared with those of the vehicle control group using
Student's t-test (fetal weight) or chi-square test (others).
Toxicokinetic study
Pregnant mice were treated with 20 pmol alltruns-RA or all-trans-RAGlkg b.wt. on GD 11 as described for the teratologic study. To examine retinoid
pharmacokinetics in the plasma of one group of mice,
serial blood samples were collected under brief ether
anesthesia from the retroorbital sinus into heparinized
capillary tubes 0.25,0.5,1,2,4,8,16,24,32, and 48 hr
after treatment. Plasma was prepared by centrifuga-
152
H. NAU ET AL.
TABLE 1. Prenatal effects induced by all-trans-RA or all-trans-RAG (both
20 pmolkg, s.c.) in NMRI mice on GD 11
No. of litters
Implantations
Resorptions
Live fetuses
Fetal weight ( g k SD)
Exencephaly
Kinked tail
Full-length cleft palate'
Dislocated hind limb
Extra ribs'
Dislocated sternum2
Radius (bent)'
Radius (short)'
Ulna (bent)
Control' (%)
9
110
13 (11.8)
97 (88.2)
1.30? 0.11
0 (0)
0 (0)
0 (0)
3 (3.1)
10 (10.3)
9 (9.28)
(0)
(0)
(0)
(0)
all-trans-RA(%)
9
108
6 (5.6)
102 (94.4)
1.24 f 0.13**
(0)
l(0.98)
4 (3.9)*
6 (5.9)
15 (14.7)
14 (13.7)
(0)
(0)
(0)
all-trans-RAG (%)
12
142
16 (11.3)
126 (88.7)
1.23 f 0.11**
2 (1.6)
0 (0)
27 (21.4)**
4 (3.2)
62 (49.2)**
40 (31.7)**
25 (19.8)**
12 (9.5)**
4 (3.2)
3 (2.4)
Ulna (short)
(0)
'One ml DMSOkg b.wt. S.C.
'Significantly higher in the all-trans-RAG-treatedgroup than in the all-tram-RA-treated
group.
*P < 0.05;**P< 0.01;compared with the control group using the Student's t-test (fetal
weight) and chi-squaretest (others).
tion of the blood for 10 min at 1,500g and 4°C. Two
other groups of mice were also administered all-transRAG as described. These animals were killed by cervical dislocation 2 and 6 hr after treatment, respectively,
after blood had been collected. Plasma was prepared
from this blood as described, and embryos, yolk sacs,
placentas, and maternal livers, kidneys, and spleens
were collected. To reduce their blood content, liver
samples were rinsed with ice-cold 0.9% (w/v) aqueous
NaCl solution. All tissues were weighed and immediately frozen.
For examination of plasma retinoid concentrations
at different time points after intravenous 6v.) administration, non-pregnant (female) mice were administered the all-trans-RAG solution or an equimolar solution of all-trans-RA in DMSO. They received a single
i.v. dose (injected into the tail vein) of 5 kmol/kg (corresponding to 10 p1 dosing solution per mouse).
(eluent A: water + 0.2% trifluoracetic acid; eluent B:
acetonitrile + 0.2% trifluoracetic acid) which has been
developed especially for separation of isomers of retinoyl-f3-D-glucuronide and retinoic acid (Sassand Nau,
'94). Calibration was performed using solutions of bovine serum albumin spiked with defined concentrations of reference compounds. Plasma AUC values
were calculated using the trapezoidal rule.
RESULTS
Teratology
Both all- trans-RA and all-truns-RAG were administered on GD 11 in the NMRI mouse with a dose of 20
kmol/kg b.wt. As expected, this administration regimen was clearly teratogenic with all-trans-RA and a
number of retinoid-specific malformations were observed such as limb defects, other skeletal defects, and
cleft palate (Table 1). The fetal weight was slightly
reduced by both drugs, and the embryolethality was
Retinoid analysis
not affected.
Plasma, embryo, and yolk sac samples were exSurprisingly, all-trans-RAG exhibited a higher tertracted with a threefold volume of isopropanol, folatogenic potency compared to all-trans-RA: retinoidlowed by solid phase extraction according to the
specific malformations such as limb reduction defects
method described by Collins et al. ('92). Analytes were
and cleft palate were more pronounced after applicaenriched on AASP C2 solid phase extraction cartridges
tion of all-trans-RAG than after all-trans-RA (Table I).
(silica modified with ethyl groups; ICT, Bad Homburg,
Germany). Sample preparation of maternal tissues was
Toxicokinetics
based on this method. However, prior to extraction
I.v. administration. All-trans-RA as well as allwith isopropanol, the tissues-except livers-were homogenized in an equal volume of water. If necessary, trans-RAG, dissolved in DMSO, were administered to
tissues were minced with scissors before homogeniza- non-pregnant mice via the i.v. route. The concentration. Livers were homogenized with 9 volumes of ice- tions observed in plasma are shown in Figure 1.
cold 0.9% (w/v) NaCl solution in a teflon-glass potter. Both drugs reached high initial concentrations. AllFollowing solid phase extraction, retinoid concentra- trans-RA was rapidly cleared, while the elimination of
tions were determined with a reversed phase high per- all-trans-RAG from mouse plasma proceeded much
formance liquid chromatographic (HPLC) method more slowly. Most importantly, considerable concen-
ALL-TRANS-RETINOYL-P-GLUCURONIDE 153
A
B
all-trans-RAG i.v.
all-trans-RA i . v .
104,
all-trans-RAG
103
102,
100
I
0
1
2
3
4
5
6
0
1
2
3
4
5
6
Time [hours]
Time [hours]
Fig. 1. Plasma concentrations of retinoids following i.v. administration of 5 pmoykg b.wt. all-transRAG (A) or all-trans-RA (B) in NMRI mice.
1 o3
,RAG
lo3
1 o2
a I I - trans-RA
10'
I
0
.
I
'
I
'
I
*
I
2
4
6
8
Time [ h o u r s ]
10'
0
2
4
6
8
Time [ h o u r s ]
F5g. 2. Plasma concentrations of retinoids (mean ? SD, n = 3-6) following 8.c. administrationof 20
pmol/kg b.wt. all-trans-RAG(A) or all-trans-RA (B) in NMRI mice; samples from retro-orbital sinuses.
Kinetic analysis yields elimination half-lives for all-trans-RA and all-trans-RAG of 2.6 and 3.0 hr,
respectively.
154
H.NAU ET AL.
present in the embryo in minute concentrations only in
spite of high maternal plasma levels (Table 3). In contrast, high concentrations of both all-trans-RA and alltrans-RAG were found in kidney, which even exceeded
AUC,-,h, (FMhr)
maternal
plasma levels. Considerable levels of both
Administration of
All-trans-RA
All-trans-RAG
all-trans-RA
and all-trans-RAG were observed in liver,
All-trans-RA (n = 6)
0.44 f 0.11
Trace
placenta,
yolk
sac, and spleen. Other isomers of RA and
2.04 f 1.07*
8.84 f 1.48
All-trans-RAG (n = 3)
RAG were present in plasma and tissues in much lower
*Significantlyhigher than the AUC of all-trans-RAfollowing concentrations.
administrationof all-trans-RA(P < 0.01; Student's two-tailed
t-test).
DISCUSSION
The most important finding of the present study was
trations of all-trans-RA were found in plasma after administration of all-trans-RAG. Some hemolysis of the the high teratogenicity observed in mice following adblood was observed after i.v. application of the drug ministration of all-trans-RAG. The teratogenic potency
of all-trans-RAG exceeded that of all-trans-RA in the
preparations as well as the pure vehicle (DMSO).
S.C. application. Plasma retinoid levels following experimental protocol of the present study. These reS.C. application of all-trans-RA and all-trans-RAG to
sults are readily explained by our toxicokinetic study:
mice are shown in Figure 2. Again, high initial con- all-trans-RA levels and AUC values following admincentrations of all-trans-RAG (Fig. 2A) as well as all- istration of all-trans-RAG were high because of contintrans-RA (Fig. 2B) were observed after application of uous hydrolysis of persistent all-trans-RAG levels. In
the respective drugs. All-trans-RA was cleared rapidly contrast, all-trans-RA administration resulted in rapid
after all-trans-RA administration, while all-trans-RAG clearance of this compound. Similar findings were obwas cleared more slowly. Again, considerable all- served after S.C. as well as i.v. administration regitrans-RA levels were observed after all-trans-RAG ap- mens. It is thus clear that all-trans-RAG acts as a preplication (Fig. 2A). The plasma concentrations of all- cursor for all-trans-RA, which is formed via hydrolysis
trans-RAG following all-trans-RA application were in the maternal organism and can transfer to the emvery low. Little hemolysis was observed after S.C.ap- bryonic compartment and act as a teratogen.
Previous studies showed that all-trans-RAG and its
plication of the DMSO preparations.
The plasma and tissue concentrations of retinoids isomers-formed as metabolites from the respective
found 2 and 6 h r after administration of all-trans-RAG retinoic acid-transfer to the embryo in small concento pregnant mice are shown in Tables 2 and 3. The trations only: in several species (mouse, rat, rabbit,
plasma AUC values after administration of the drug monkey) embryonic/maternal plasma ratios of allconjugate (Table 2) were 8.84 p M h r all-trans-RAG and trans-RAG were well below 0.1. It was therefore hoped
2.04 pM/hr all-tram-RA. The elimination half-life of that all-tram-RAG would be a n interesting retinoid
all-trans-RAG in maternal plasma, determined from with low teratogenic activity. Our present results demthe data displayed in Figure 2A, was 3.0 h r (r = onstrate, however, that all-trans-RAG is readily hydro0.9999 for 2-8 hr). As expected, all-trans-RA exhibits lyzed to the teratogenic all-trans-RA after S.C. as well
good transfer to the embryo, while all-trans-RAG was as i.v. administration. All-trans-RAG is therefore a
TABLE 2. Plasma AUC values following
administration of all-trans-RAor all-trans-RAG(both
20 pmolkg, s.c.) in NMRI mice on GD 11
TABLE 3. Plasma and tissue concentrations (nM) following S.C.administration of 20 pmoykg b.wt. all-trans-RAG
to pregnant mice on GD 11
Plasma/
tissue
Plasma
Embryo
Yolk sac
Placenta
Liver
Kidney
Spleen
Time after
administration (hr)'
All-trans-RAG
2
6
2
6
2
6
2
6
2
6
2
6
2
6
1,703 f 674
854 193
18.5 4.2
37.2 f 15.2
465 2 199
482 f 227
634 t 256
883 -t 224
1,017 f 536
1,023 2 69.5
3,254 f 249
3,372 f 762
385 t 344
193 f 82.0
*
*
13-cis-RAG
Concentrations (nM)
9-cis-RAG All-trans-RA
46.4
25.5
64.9 17.6
26.6 f22.7
* 30.5
* 15.9
-2
*
-
-2
-2
-2
<20
20.9 L25.4
<20
21.1 k23.9
-
-
115 f 19.5
195 62.4
291 41.6
8.90 7.0
7.60 2 3.3
111 2 16.8
106 f 29.2
132 f 17.2
20.5 7.2
11.7 3.9
'N = 5 mice (2 hr); N = 4 mice (6 hr).
'Small peaks and/or overlapped by interfering fractions.
*
*
*
*
*
*
*
555 91.2
14.8 2.8
424 f 226
23.9 t 4.9
378 f 208
21.2 2 9.6
468 f 144
-
4,070 f 1,051
729 2 89.3
2,003 t 71
123 f 24.0
307 f 191
-
13-cis-RA
23.9 6.5
9-cis-RA
9.73 7.3
23.6 +. 10.9
27.5 f 14.9
27.9 f 17.7
18.3 k24.7
4.02 2 2.7
*
-
-
-2
*
-
-
18.2 ? 7.3
-
-2
-2
307 +. 220
258
58.1 2 15.4
34.1 ? 9.9
21.1 k23.4
-
-
2
-
-
161
ALL-TRANS-RETINOYL-P-GLUCURONIDE 155
precursor for all-trans-RA after systemic application,
and the hoped-for advantage of all-trans-RAG over alltrans-RA in regard to an improved safety ratio is not
seen. The recent report that all-trans-RAG is of low
teratogenicity after oral application in rats (Gunning
et al., '93) must be interpreted with great caution: alltrans-RAG was only poorly absorbed under the experimental protocol used in that study (oral application).
Our present study (s.c. application) clearly shows that
all-trans-RAG, if absorbed, is a potent teratogen in
vivo.
Further experiments need to be undertaken to show
if all-trans-RAG has a n advantage over all-trans-RA in
other administration regimens. All-trans-RAG has
been described to be less irritant to skin than alltrans-RA following topical application; however, much
higher dosages of topical all-trans-RAG than topical
all-trans-RA had to be used to exert a pharmacological
effect (Gunning et al., '94). The possible systemic exposure to all-trans-RA following topical all-trans-RAG
application has not yet been studied. The present results suggest that all-trans-RAG will be teratogenic if
available systemically and that this retinoid should not
be used in women of childbearing age until a formulation can be developed which exerts the desired pharmacological activity, but does not result in systemic
retinoid exposure.
ACKNOWLEDGMENTS
This work was supported by the European Commission (BIOTECH program BI02-CT93-0471). The excellent technical assistance of C. Plum (HPLC) and I. Dillmann (teratology) is gratefully acknowledged. U.
Schwikowski prepared the glossy prints of the figures.
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