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Vol. 26, Issue 3, 234-239, March 1998
Department of Drug Safety and Disposition, Ligand Pharmaceuticals, Inc.
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Abstract |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Retinoids are compounds that bind to and activate one or more retinoid receptors to elicit various physiological responses. There are two families of retinoid receptors, i.e. retinoic acid receptors (RAR) and retinoid X receptors (RXR), for which the various synthetic and naturally occurring retinoids have differing selectivities. The synthetic analogs LG100268 and LGD1069 (Targretin) are RXR-selective, whereas ALRT1550 is highly RAR-selective. Naturally occurring all-trans-retinoic acid (Tretinoin) has a degree of selectivity for RAR, whereas ALRT1057 (9-cis-retinoic acid, Panretin) is equally active at RAR and RXR (i.e. a pan-agonist). To evaluate the effects of these compounds on metabolic enzymes, male Sprague-Dawley rats received daily oral doses for 4 days, and liver microsomes were prepared on day 5. As a class, these ligands exerted profound effects on hepatic microsomal metabolic enzyme levels. Those with RAR activity decreased hepatic cytochrome P450 (CYP or P450) levels and in vitro metabolism of the compound of pretreatment, whereas those exerting predominantly RXR activity increased these parameters. A similar relationship was observed when glucuronidation was examined. Hepatic CYP2B1/2 was unaffected and CYP3A was decreased by RAR-selective ALRT1550, whereas both were induced by ligands selective for RXR. However, both RAR- and RXR-selective ligands decreased CYP1A2, whereas they induced CYP4A. Although the mechanisms underlying these effects are not known, these results suggest that RAR- and RXR-binding ligands exert distinct effects on hepatic metabolism, and they indicate the potential for drug-drug interactions, especially involving CYP3A. The nature of such interactions would depend on the RAR/RXR selectivity of the ligand and the P450 isozymes responsible for the metabolism of coadministered drugs.
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Introduction |
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Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Retinoids are
compounds that bind to and activate one or more of the known nuclear
retinoid receptor subtypes, to modulate gene expression. A number of
compounds in this class are being investigated for use as
chemopreventive and chemotherapeutic agents (Gudas et al.,
1994
) and have been used clinically to treat promyelocytic leukemia,
leukoplakia, severe acne, and other skin conditions (Orfanos et
al., 1987; Smith et al., 1992; Vokes et al.,
1993). As research progresses in this exciting field, new biological effects and potential therapeutic uses continue to be identified.
The molecular mechanisms by which retinoids exert their effects are
complex. There are two classes of retinoid receptors, RAR1 and RXR, within each
of which three subtypes (
, 
, and 
) are recognized. Numerous
synthetic and endogenous retinoid receptor-binding ligands, which
display varying affinities for these receptors, have been identified;
the term "rexinoid" has been coined to refer to compounds that are
selective for RXR, and it has been proposed that the term
"retinoid" be reserved for ligands that bind RAR (Mukherjee
et al., 1997). Whether bound or unbound by ligand, RXR can
either form homodimers or heterodimerize with other ligand-bound nuclear receptors, such as the RAR, PPAR, vitamin D receptor, thyroid
hormone receptor, or "orphan receptors" (receptors for which no
endogenous ligand is known) (Chambon, 1996). This dimer formation is
necessary for the activity of these receptors, making RXR a key
regulator of the activity of nonsteroidal nuclear receptors, including
RAR and RXR itself (Mangelsdorf and Evans, 1995). Considering this role
of RXR, it is obvious that the relative activities of retinoids at RAR
and RXR may have profound effects on their overall biological effects.
Examples of this relationship include the correlations between the RAR
and RXR selectivity of ligands and their lipid-modulating (Standeven
et al., 1996; Vu-Dac et al., 1996),
cell-differentiating (Boylan et al., 1995), apoptotic (Boehm et al., 1995), antiproliferative (Zhang et al.,
1996), and insulin-sensitizing (Mukherjee, et al., 1997)
effects.
In addition to being metabolized by rat hepatic P450 enzymes (Genchi
et al., 1996) and GT (Genchi et al., 1996; Sass
et al., 1994), retinoids can affect P450 levels (Li et
al., 1995; Tsambaos et al., 1994; Goerz et
al., 1994; Westin et al., 1993) and hepatic GT activity
(Rozman et al., 1987). Moreover, retinoids have been shown
to modulate the activity of genes involved in oxidative metabolism
(Duell et al., 1992; Duester et al., 1991; Vanden
Bossche et al., 1988) and, specifically, to affect
transcription of the gene for CYP1A1 (Vecchini et al.,
1994). However, the detailed nature of these effects, and especially
the relative importance of RAR and RXR activity in their expression, is
not known. The present study was undertaken to assess, in rats, the
effects of treatment with a number of ligands, with a range of RAR/RXR
selectivities, on total P450 levels and P450 isozyme profiles. In
addition, the effects of treatment with these compounds on their own
rate of metabolism by P450, as well as GT, in hepatic microsomes were evaluated.
Five ligands were examined for their effects on drug-metabolizing
enzymes. Of the five, two are considered rexinoids; LG100268 has the
greatest selectivity for RXR (Ki for RXR
>333-fold lower than that for RAR), whereas the RXR selectivity of
LGD1069 (Targretin) is somewhat less (Ki
for RXR >35-fold lower than that for RAR) (Boehm et al.,
1995). ALRT1057 (9-cis-retinoic acid, Panretin) is equally
active at RAR and RXR (i.e. a pan-agonist), whereas ATRA
(Tretinoin) has a degree of selectivity for RAR
(Ki for RAR about 30-fold lower than that
for RXR) and ALRT1550 is highly RAR-selective
(Ki for RAR about 300-fold lower than that
for RXR) (Zhang et al., 1996). The in vivo
receptor selectivity of LG100268 (Standeven et al., 1996)
and LGD1069 (Gottardis et al., 1996) has been demonstrated
at the dose ranges used in the current study; the higher dose of
LGD1069 was used because the potency of LGD1069 at RXR is 5-8-fold
lower than that of LG100268 (Boehm et al., 1995). Based on
literature data (Collins et al., 1994), ATRA administered to
rats at 30 mg/kg/day should produce plasma concentrations that preferentially activate RAR (Ki = 17-19
nM) over RXR (Ki = 290-880 nM) (Zhang
et al., 1996). Finally, an oral dose of 0.05 mg/kg/day of
ALRT1550 has been shown to exert significant RAR-mediated effects in
rats (Ligand Pharmaceuticals, Inc., data on file), and the peak plasma
concentration projected to result from such a dose (~20 nM) should
not stimulate RXR (Ki = 223-560 nM)
(Boehm et al., 1995).
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Materials and Methods |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Photolabile Retinoids. For the photolabile retinoids used in this study (ALRT1550, ATRA, and ALRT1057), all procedures were conducted under subdued ambient light, to minimize isomerization.
Chemicals.
ATRA, PEG 400, CMC, Tris-HCl, KCl, sucrose, potassium phosphate,
EDTA, protein standards, NADP, UDP-glucuronic acid,
MgCl2, ammonium acetate, glucose-6-phosphate
dehydrogenase, glucose-6-phosphate, -glucuronidase, D-saccharic
acid-1,4-lactone, Brij 58, and fetal BSA were purchased from Sigma
Chemical Co. (St. Louis, MO). ALRT1550 [(2E,4E,6E)-7-(3,5-di-tert-butylphenyl)-3-methylocta-2,4,6-trienoic acid], ALRT1057 (9-cis-retinoic acid), LGD1069
[4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethenyl]benzoic acid], and LG100268
[6-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)cyclopropyl]nicotinic acid] (fig. 1) were provided by the
Departments of Retinoid Chemistry Research or Chemical Development,
Ligand Pharmaceuticals, Inc. (San Diego, CA). Acetonitrile, glacial
acetic acid, and Tween 80 were purchased from VWR Scientific Products
(San Diego, CA).
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Animal Treatment and Preparation of Microsomes.
All drugs were formulated as aqueous microparticulate suspensions in
9.95% PEG 400/0.05% Tween 80/0.9% CMC/89.1%
water (v/v/w/v). The formulation was prepared by dissolving drug in
ethanol, adding PEG 400 (containing 0.5% Tween 80), and then diluting
the solution with water during vortex-mixing to precipitate the drug.
Ethanol and water were removed in vacuo using a Rotavapor
evaporator (Buchi RE111) maintained at 30°C, leaving a
microparticulate suspension in PEG 400 and Tween 80. To the
microparticulate suspension were added 9 volumes of 1% CMC. Dosing
suspensions were prepared on the first day of the study and stored in a
refrigerator at 
2-5°C throughout the study.
. Livers were homogenized in 50 mM Tris-HCl (pH 7.4) containing
150 mM KCl and 2 mM EDTA. Microsomes were prepared by
ultracentrifugation (100,000g for 60 min) of the
postmitochondrial supernatant (10,000g for 20 min). The
first microsomal pellet was resuspended in 10 mM EDTA (pH 7.4)
containing 150 mM KCl and was reisolated by ultracentrifugation. The
washed microsomes were suspended in 250 mM sucrose and stored at
70°C.
Determination of Microsomal Protein and P450 Concentrations.
Protein concentrations in the microsomal samples were determined using
a Sigma Diagnostics kit (procedure 541; Sigma) based on the biuret
reaction assay (Doumas et al., 1981). The absorbance of
standards and samples was measured at 595 nm. P450 concentrations were
determined from difference spectra of the reduced protein at 450 nm
(Omura and Sato, 1964), obtained using a Uvikon 941 spectrophotometer
(Kontron Instruments, Zurich, Switzerland).
Western Blot Immunoassays. The relative levels of various P450 isozymes in the microsomes were measured by Western blot analysis conducted using Amersham Life Science ECL kits (Amersham International plc, Buckinghamshire, UK), which, except for CYP2C11, included the primary antibody. For CYP2C11, the primary antibody was obtained from Oxford Biomedical Research (Oxford, MI) or Gentest Corp (Woburn, MA) and the secondary antibody was obtained from Sigma. For each P450 isozyme, microsomes from control and treated rat livers were analyzed on the same gel, to allow evaluation of the effect of treatment without measurement of absolute concentrations. The amount of microsomal proteins loaded onto the gels was varied, based on data from preliminary experiments, from 10 to 60 µg, to maintain the responses in a linear range. Proteins were separated by 12% sodium dodecyl sulfate-polyacrylamide electrophoresis and were electrophoretically blotted onto nitrocellulose membranes. Blots were incubated first with primary anti-P450 and then with secondary antibody followed by streptavidin-horseradish peroxidase. Finally, detection reagents were added to the membrane, which was then placed on photographic film for 5 min. After film development, the integrated densities of the resultant bands were determined using a densitometer.
Measurement of Microsomal Metabolism Rates. P450- and GT-mediated metabolism rates were determined in separate experiments. Six replicate tubes were used for each rat in each group. After the reaction had been started (in the case of P450, by addition of NADPH-generating solution; in the case of GT, by addition of UDP-glucuronic acid), the incubation was quenched immediately in three tubes and after various periods in the remaining three tubes. The rate of metabolism was measured by quantifying the metabolites formed over time, using HPLC with UV detection. For LGD1069, ALRT1057, and ATRA, these metabolites were 6/7-hydroxy-LGD1069, 4-hydroxy-ALRT1057, and 4-hydroxy-ATRA, respectively, for P450 incubations or acyl glucuronides for glucuronidation incubations. The chemical structures of the ALRT1550 and LG100268 metabolites remain unproven but are presumed to be monohydroxylated or acyl-glucuronidated as well. Assay parameters (substrate concentration and incubation time) were optimized for each substrate so that incubations were conducted under initial-rate conditions (data not shown).
For determination of P450-mediated metabolism, the assay mixtures contained the following, in a final volume of 0.5 ml: 1 mg/ml microsomal protein, 100 mM potassium phosphate buffer (pH 7.4), 1 mM EDTA, 1 mM MgCl2, 1% BSA, 5 mM glucose-6-phosphate, 1 mM NADP, and 1 unit/ml glucose-6-phosphate dehydrogenase. The final concentrations of ALRT1550, ATRA, ALRT1057, LGD1069, and LG100268 in the incubation were 40, 13, 18, 100, and 50 µM, respectively. After 30, 20, 20, 6, or 15 min, respectively, each reaction was stopped by addition of 1 ml of ice-cold ethanol. For determination of GT-mediated metabolism, the assay mixtures contained the following, in a final volume of 0.5 ml: 1 mg/ml microsomal protein, 200 mM Tris buffer (pH 7.4), 10 mM MgCl2, 1.25 mM D-saccharic acid-1,4-lactone, 0.05% (w/v) Brij 58, and 1% BSA. The final concentrations of ALRT1550, ATRA, ALRT1057, LGD1069, and LG100268 in the incubation were 40, 100, 100, 65, and 50 µM, respectively. Reactions were initiated by the addition of UDP-glucuronic acid. After 30, 60, 60, 20, or 15 min, respectively, the reaction was stopped by addition of 1 ml of ice-cold ethanol.Chromatographic Analysis.
After quenching with ethanol, microsomal samples were chilled at
20°C for at least 1 hr. After centrifugation, 1-ml aliquots were
evaporated under a nitrogen stream or, for ALRT1550, ATRA, and
ALRT1057, in vacuo using a Savant model AS290 SpeedVac
concentrator (Savant Instruments, Inc., Farmingdale, NY). Samples were
reconstituted in 250 µl of 40% acetonitrile in 10 mM ammonium
acetate/glacial acetic acid (100:1). Reverse-phase gradient HPLC
(Hewlett-Packard model 1050), with a Microsorb-MV
C18 analytical column (5 µm, 4.6 × 250 mm; Rainin Instrument Co., Woburn, MA) maintained at 40°C, was used
to separate the retinoids and their metabolites. For ALRT1550, LGD1069,
and LG100268, the solvent gradient was ramped linearly from 20 to 80%
acetonitrile/glacial acetic acid (100:1) in 10 mM ammonium
acetate/glacial acetic acid (100:1) over 20 min and was then maintained
for an additional 15 min at 80% acetonitrile. For ATRA and ALRT1057,
the solvent gradient was ramped linearly from 65 to 100%
acetonitrile/glacial acetic acid (100:1) in 10 mM ammonium
acetate/glacial acetic acid (100:1) over 11 min and was then maintained
for an additional 5 min at 100% acetonitrile. Peak detection for
ALRT1550, ATRA, ALRT1057, LGD1069, and LG100268 metabolites was at 340, 348, 348, 262, and 281 nm, respectively.
Data Analysis. Statistical analyses were performed using Student's t tests; p values of <0.05 were considered statistically significant.
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Results |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Effect of Treatment on Microsomal Metabolism. As a class, these compounds exerted significant effects on their own P450-mediated metabolism (fig. 2). Decreases in the P450-mediated metabolism of ALRT1550 and ATRA were seen in microsomes from rats treated with these retinoids, although the effect of ATRA treatment was not statistically significant (p = 0.06). The pan-agonist ALRT1057 did not affect its own P450-mediated metabolism, whereas treatment of rats with LGD1069 or LG100268 resulted in increased rates of metabolism of these rexinoids. The same pattern was seen for GT-mediated metabolism, except that ATRA caused a significant decrease in its own glucuronidation (fig. 3).
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Effect of Treatment on Total P450 Concentration. Corresponding to the observed changes in metabolic rates, ligands with significant RAR activity (ALRT1550, ATRA, and ALRT1057) tended to decrease hepatic microsomal P450 levels in rats, whereas the rexinoids increased P450 (fig. 4).
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Effect of Treatment on P450 Isozyme Content. Mixed results were obtained regarding effects on individual P450 isozymes (fig. 5). Most of the compounds tested induced some isozymes while reducing the levels of others; the exception was ATRA, which did not induce any isozyme. Examination of the data on an isozyme-by-isozyme basis revealed that some isozymes were affected similarly by all five ligands. For example, with the exception of ATRA, all ligands caused significant induction of microsomal CYP4A, although the magnitude of induction was greater with the rexinoids (16- and 72-fold increases with LGD1069 and LG100268, respectively). Conversely, microsomal CYP1A2 was decreased by all five ligands, although the effect was not statistically significant for ATRA or ALRT1057. Other isozymes responded differently to different compounds. Two isozymes appeared to be affected according to the RAR/RXR selectivity of the ligand. Microsomal CYP2B1/2 was induced by compounds with RXR activity, including ALRT1057, but was unaffected by the RAR-selective compounds. Similarly, CYP3A levels were induced by the rexinoids, but compounds without RXR selectivity did not affect CYP3A levels. However, unlike CYP2B1/2, CYP3A levels were decreased 70% by the RAR-selective ALRT1550. The effects on microsomal CYP2C11 varied without discernible patterns, and the effects on CYP2E were limited to roughly 30% reductions by ATRA and ALRT1057.
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Discussion |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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The existence of interactions between retinoids and P450 and GT
systems is well established; retinoids both affect and are metabolized
by these systems. The potential for the metabolism of retinoids to be
affected by alterations in P450 and GT enzyme levels (caused by
pretreatment with either themselves or other drugs) is demonstrated by
the induction of the P450-mediated metabolism of ATRA by dexamethasone
and phenobarbital (Martini and Murray, 1994) and the induction of the
glucuronidation of ATRA by 3-methylcholanthrene and clofibrate (Genchi
et al., 1996; Sass et al., 1994). In addition, P450 inhibitors have been shown to prolong the in vivo
half-life of ATRA in rats (Van Wauwe et al., 1988, 1990) and
mice (Achkar et al., 1994). Therefore, the potential for
drug-drug interactions, as well as alterations in their own metabolism
after repeated administration, is clearly evident for the retinoids.
However, very little is known about either the nature of the effects of retinoids on these metabolic enzyme systems or the relationship between
RAR/RXR selectivity and these effects. Considering the very different
actions of RAR agonists and RXR agonists in other biological systems,
it might be anticipated that retinoids with differing activities at RAR
and RXR would have distinct effects on the P450 and GT systems. In the
present work, five retinoid receptor ligands with activities ranging
from highly RAR-selective to highly RXR-selective were evaluated for
their effects on their own phase I and phase II metabolism and on
hepatic P450 isozyme profiles. The results clearly demonstrate that, as
a class, retinoid receptor ligands affect their own phase I and phase
II metabolism and exert profound effects on hepatic P450 isozyme
profiles. Because properties other than their RAR/RXR selectivities, or
even their actions at retinoid receptors, might have led to the effects
observed, these data do not prove that RAR activity is associated with
certain effects on these enzymes whereas RXR activity is associated
with other effects. In addition, the magnitude of the effects induced by the various retinoids depends on their relative potencies at the
retinoid receptors and the drug concentrations achieved at the
receptors, which are functions of the administered doses and the
pharmacokinetic characteristics of the compounds. Much more extensive
studies would be required to evaluate the relative potencies of the
different ligands to produce the observed effects. Qualitatively, however, the actions of these ligands on these enzymes are evident.
Based on the effects of repeated treatment on P450, GT, and the
metabolism of the compound used for treatment, it appears that RAR
activation leads to decreased microsomal metabolism, mediated by
decreases in enzyme concentrations, whereas RXR activation enhances
microsomal metabolism by increasing these enzymes. The case of ATRA is
of special interest, because it has been found that, in the treatment
of cancer, continuous administration of ATRA results in a loss of
effectiveness ("retinoid resistance") resulting from progressive
decreases in plasma concentrations (Muindi et al., 1994).
Although ATRA metabolism is mediated in part by P450, the present data
indicate that, as measured as the total enzyme level, isozyme levels,
and activity for the metabolism of ATRA, P450 is not induced by ATRA,
at least in rats. Lipid hydroperoxides and cellular retinoic
acid-binding protein are cellular components that both accelerate the
metabolism of ATRA and are inducible (Muindi and Young, 1993; Fiorella
and Napoli, 1994; Cornic et al., 1992). Among other
possibilities, it may be that alterations in these substances, and not
induction of P450, are responsible for clinical retinoid resistance.
Generally, the trends for total P450 were reflected in overall isozyme
levels and were probably driven by the observed changes in CYP2C11 and
CYP3A, because these isozymes constitute approximately 50% of total
P450 in the livers of mature male rats (Waxman et al.,
1985). The effects on CYP2B1/2 and CYP3A were clearly correlated with
RAR/RXR selectivity; these isozymes were unaffected (CYP2B1/2) or
decreased (CYP3A) by RAR-selective compounds but induced by rexinoids.
The effects on CYP3A were particularly dramatic, ranging from a 70%
decrease after treatment with RAR-selective ALRT1550 to a 5-9-fold
induction after rexinoid treatment. CYP3A is also involved in the
metabolism of LGD1069 in rats (Hein et al., 1996), so that
autoinduction of this isozyme likely leads to the decreased drug
concentrations seen after repeated administration of LGD1069 to rats
(Ligand Pharmaceuticals, Inc., data on file). CYP3A4, as the major
constitutive isoform present in adult human liver and the isozyme
responsible for the metabolism of a wide range of xenobiotics (Wrighton
and Stevens, 1992), is a common mediator of drug-drug interactions.
Therefore, if retinoid receptor-binding ligands cause changes in P450s
in humans similar or analogous to those they cause in rats, they could
alter the metabolism of themselves or coadministered drugs; the nature
of these changes would depend on the RAR/RXR selectivity of the ligand
and the P450 isozymes responsible for the metabolism of coadministered drugs.
The mechanisms underlying the effects of these compounds on P450 levels
await further study. The correlation between RAR/RXR selectivities and
effects on microsomal metabolism and P450, GT, CYP2B1/2, and CYP3A
levels indicates that RXR activation may modulate drug-metabolizing
enzymes. Whether effects of RXR activation on drug-metabolizing enzymes
might be mediated through enhanced RXR homodimer formation, enhanced
heterodimer formation with unknown partners, or sequestration of RXR in
homodimer form (Pfahl and Chytil, 1996) is not known. The situation is
complicated by the observation that, for several isozymes, there is no
apparent correlation between RAR/RXR selectivity and the effect of
treatment, indicating that factors other than RAR and RXR selectivity
are involved in these effects. The correlation between RXR activity and
induction of CYP4A is not surprising, because peroxisome proliferators
are known to induce this isozyme (Gibson, 1989) and the RXR-PPAR
heterodimer activates this signaling pathway (Schoonjans et
al., 1996; Aldridge et al., 1995); in addition, RXR
ligands alone can activate the heterodimer (Kurokawa et al.,
1993). The effect of the RAR-selective ALRT1550 to induce CYP4A is not
as easily understood, because RAR is not known to form heterodimers
with PPAR; this finding invites further study.
In summary, retinoid receptor-binding ligands have profound and mixed effects on rat liver drug-metabolizing enzymes and on their own metabolism. RXR activity appears to enhance, and RAR activity appears to decrease, microsomal phase I and II metabolism of these compounds and the levels of some isozymes. Regardless of the mechanisms involved, the complex effects on P450 isozyme profiles indicate that compounds in this class have the potential to interact with the metabolism of coadministered drugs that are metabolized by P450.
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Footnotes |
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Received June 30, 1997; accepted November 21, 1997.
Send reprint requests to: Stanley R. Howell, Department of Drug Safety and Disposition, Ligand Pharmaceuticals, Inc., 10255 Science Center Drive, San Diego, CA 92121.
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Abbreviations |
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Abbreviations used are: RAR, retinoic acid receptor(s); RXR, retinoid X receptor(s); GT, glucuronyltransferase; ATRA, all-trans-retinoic acid; BSA, bovine serum albumin; CMC, carboxymethylcellulose; CYP or P450, cytochrome P450; PPAR, peroxisome proliferator-activated receptor(s); PEG, polyethylene glycol.
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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(RAR) and RAR results in receptor-specific alterations in retinoic acid-mediated differentiation and retinoic acid metabolism.
Mol Cell Biol
15:
843-851[Abstract]. -glucuronides and of -galacturonides of various retinoids catalyzed by induced and noninduced microsomal UDP-glucuronosyltransferases of rat liver.
Biochem Biophys Acta
1289:
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