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10.1146/annurev.ecolsys.36.102003.152617

Annu. Rev. Ecol. Evol. Syst. 2005. 36:169–89
doi: 10.1146/annurev.ecolsys.36.102003.152617
c 2005 by Annual Reviews. All rights reserved
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THE INFLUENCE OF PLANT SECONDARYMETABOLITES ON THE NUTRITIONAL ECOLOGYOF HERBIVOROUS TERRESTRIAL VERTEBRATES
M. Denise Dearing,1 William J. Foley,2 and Stuart McLean3
1
Department of Biology, University of Utah, Salt Lake City, Utah 84112;
email: dearing@biology.utah.edu
2School of Botany and Zoology, Australian National University, Canberra ACT 0200,
Australia; email: william.foley@anu.edu.au
3
School of Pharmacy, University of Tasmania, Hobart, Tasmania 7005, Australia;
email: Stuart.McLean@utas.edu.au

Key Words biotransformation, conditioned food aversions, conjugation,functionalization, permeability glycoprotein, regulated absorption■ Abstract Plant secondary metabolites (PSMs) significantly impact the nutritional
ecology of terrestrial vertebrate herbivores. Herbivores have a wide range of mechanisms (herbivore offenses) to mitigate the negative effects of PSMs. We discuss several
behavioral and physiological offenses used by terrestrial vertebrates. Several newly recognized herbivore offenses such as regulated absorption and regulation of toxin intake
are presented. We give a detailed description of the biotransformation system withrespect to PSMs. We also summarize recent findings of plant–animal interactions forlizards, birds, and mammals. Finally, we discuss some new tools that can be applied
to long-standing questions of plant–vertebrate interactions.

INTRODUCTION
Herbivores are faced with a food resource of poor quality not only because plants
are low in nutrients but also because they produce plant secondary metabolites(PSMs) that have wide-ranging physiological effects from direct toxicity to digestion impairment. We review the significant impact of PSMs on the nutritional
ecology of terrestrial vertebrate herbivores by beginning with a very brief introduction to PSMs. We follow with an extensive review of herbivore offenses (Karban& Agrawal 2002) including numerous behavioral and physiological mechanisms
herbivores use to deal with PSMs. We finish with a short summary of the current
state of research for three classes of vertebrate herbivores and novel tools for futurestudies. A goal of this review is to point out new avenues for research in the areaof plant–animal interactions.
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Plant Secondary Metabolites
Understanding the effects of PSMs on herbivore foraging may seem overwhelming given the bewildering variety of compounds. This diversity has led to different
classification schemes based on chemical characteristics (e.g., terpenoid, phenolic,alkaloid), modes of action (toxins versus digestibility reducers), or plant apparency(abundance). Although these classifications have been useful in formulating somebroad theories of plant defense, the more we learn, the less useful such broad classifications become (Foley et al. 1999, Foley & McArthur 1994). Most progressin the past decade in understanding how PSMs influence vertebrate herbivores
has come from systems where the plant chemistry is well characterized throughpartnerships between chemists and ecologists (e.g., Clausen et al. 1986, Jakubas &Gullion 1990, Lawler et al. 2000, Moore et al. 2004). We believe that understanding the precise nature of the chemistry mediating plant–vertebrate interactions
is extremely valuable. However, detailed chemical characterization may remainbeyond many ecological studies, which will continue to consider PSMs in broadchemical groups. Readers desiring more detail on PSM chemistry are referred to
Rosenthal & Berenbaum (1991).

MECHANISMS
In this section, we present three general mechanisms (avoidance, regulation, biotransformation) used by vertebrate herbivores to mitigate the effects of PSMs. Of
the three sections, ecologists may be least familiar with biotransformation. We
provide details of the molecular biology of biotransformation as a primer to aid
ecologists attempting to access the pharmacological literature.

Avoidance
Herbivores that cache food before consumption may behaviorally circumvent or reduce the effects of PSMs if the compounds degrade duringstorage. Behavioral reduction of PSMs prior to ingestion has a number of advantages. The detoxification system is energetically demanding (Sorensen et al.
2005a). If animals can reduce the dose of toxins consumed through food storage,
they may save significant quantities of energy that would be lost during detoxification (e.g., endogenous conjugates). Second, ingestion of lower doses may reduce
the likelihood of the formation of toxic intermediate metabolites or free radicals.
Lastly, behavioral manipulation of PSMs may enhance diet breadth by allowing
herbivores to consume plants containing toxins or concentrations of toxins thatthey would otherwise be unable to process.
A few examples of behavioral manipulation are documented. Meadow voles(Microtus pennsylvanicus) snip branches from conifer trees and delay consumption
for a few days, during which time the PSMs decrease (Roy & Bergeron 1990).
Beavers (Castor canadensis) soak twigs in water for days prior to consumption.

DECOMPOSITION

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The phenolics in the twigs are reduced through the leaching process. Beavers
prefer leached twigs to fresh twigs (Muller-Schwarze et al. 2001). Pikas (Ochotona
princeps) also manipulate the PSMs in their diet prior to consumption (Dearing
1997). In the summer, pikas preferentially collect leaves high in phenolics for
consumption during the winter. During storage, the phenolic concentrations ofleaves decay to acceptable levels. An added benefit of collecting leaves high inphenolics for storage is that these leaves preserve better, that is, there is lessdecomposition of the cache than leaves lacking phenolics.
Many herbivores produce salivary
proteins that may assuage the effects of tannins. Some tannins (condensed orhydrolyzable) react with proline-rich proteins secreted in saliva, binding to form acomplex that is usually insoluble and unabsorbed (Lu & Bennick 1998). Proline has
a secondary amine group that gives it a rigid conformation and disrupts the alphahelical structure of proteins. This makes carbonyl groups in the protein available forhydrogen bonding with the phenolic group of tannins (Santos-Buelga & Scalbert
2000). The interactions are stronger with high-molecular weight condensed tanninsthat possess many phenolic groups.
The consequences of binding tannins with salivary proteins are twofold. Tannins are inactivated as toxins, enabling the animal to eat tannin-rich browse. The
evidence that herbivores have developed specific TBSPs to bind the particulartannins found in their diet is conflicting (Hagerman & Robbins 1993, McArthur
et al. 1995). However, the increased secretion of TBSPs results in protein loss infeces, which can affect nitrogen digestibility (Skopec et al. 2004) and body weight(Santos-Buelga & Scalbert 2000). Furthermore in some species with TBSPs, therate of secretion of protein is so low as to question their role in defense against
dietary tannins (McArthur et al. 1995).

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TANNIN-BINDING SALIVARY PROTEINS (TBSP)

Regulated absorptionof PSMs by gut cells is a unique and only recently acknowledged herbivore offense (Sorensen & Dearing 2003, Sorensen et al. 2004). Absorption of PSMs
across intestinal cells can be regulated by two molecular mechanisms, a glycoprotein transporter (permeability glycoprotein, or P-gp) and a biotransformation
enzyme (cytochrome P450 3A, or CYP3A) that function either in tandem or independently to reduce the amount of PSMs absorbed. P-gp is one of a group oftransporters that remove foreign substances from cells (Hoffmann & Kroemer
2004, Lin & Yamazaki 2003). It was originally discovered in tumor cells, in which
it is responsible for resistance to several anticancer drugs (e.g., Vinca alkaloids,
taxanes). P-gp is one of a large superfamily of ATP-binding cassette transportersthat are highly conserved and found in all species from bacteria to mammals.
P-gp is highly expressed on the apical surface of cells in the lower intestine withincreasing levels from the duodenum to colon. P-gp pumps PSMs (e.g., digoxin,
morphine) back into the lumen of the gut (Hoffmann & Kroemer 2004, Lin &Yamazaki 2003). P-gp acts on hydrophobic substances, usually also containing a

PERMEABILITY GLYCOPROTEIN AND CYTOCHROME P4503A

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hydrophilic region, with a tertiary nitrogen and aromatic ring. P-gp is also present
in liver and renal tubular cells, where it pumps substances into the bile and urine,
respectively, and is in the luminal side of the capillary endothelium that forms
the blood-brain barrier (Lee & Bendayan 2004). Overall, the role of P-gp seems
to be a defense against xenobiotics such as PSMs, by opposing their absorption,
hastening their excretion, and protecting the brain. For example, mdr1a knockout
mice that lack P-gp are more sensitive to neurotoxicity from oral ivermectin than
are wild-type mice (Lin & Yamazaki 2003).
CYP3A is a biotransformation enzyme that metabolizes about 50% of all drugs
and many PSMs. It is expressed in large amounts in liver cells but also in intestinal
cells where it usually acts in concert with P-gp to reduce the absorption andbioavailability of PSMs (Cummins et al. 2002, Johnson et al. 2001). This joint
defense is most effective against toxins that are taken in low doses and which areslowly absorbed, such as the fungal metabolite, cyclosporine (Lin & Yamazaki2003). The Km values of P-gp and CYP3A are <100 µM, so PSMs present inhigh concentrations that rapidly enter intestinal cells will saturate both transporterand enzyme, resulting in dose-dependent absorption. For very lipophilic PSMs,
diffusion into intestinal cells is likely to be faster than P-gp can return them to thelumen; however, the effect of the pump will be to increase the time that the PSM
will spend in the cell, where it is exposed to metabolism by CYP3A. The result ismore extensive metabolism of the PSM rather than it being excreted unchanged in
the feces.
Only recently have P-gps been examined within the context of plant–herbivore
interactions. Several studies comparing performance of woodrats that specialize on
juniper (Neotoma stephensi) to that of a generalist woodrat (N. albigula) suggest
P-gps may play a role in dietary specialization. First, the specialist had lower
blood levels after oral dosing with α-pinene (a juniper PSM) than the generalist,
although the rates of biotransformation were not different (Sorensen & Dearing
2003). The specialist also excreted more α-pinene unchanged in the feces comparedto the generalist (Sorensen et al. 2004). Lastly, in in vitro tests, the intestinal P-gp
capacity of the specialist was significantly greater than the generalist (Green et al.
2004). Taken together, these studies suggest that the ability of Neotoma stephensi
to specialize on juniper may be in part due to P-gp and/or CYP3A that reduce
absorption of juniper toxins.
Many PSMs can act as activators, inducers, or inhibitors of P-gp and CYP3A4(Zhou et al. 2004). Exposure to enzyme inhibitors can also trigger induction. Both
P-gp and CYP3A can be induced by PSMs that bind the nuclear pregnane X
receptor (PXR) of liver and intestinal cells (Dresser et al. 2003, Kullak-Ublick &Becker 2003, Moore et al. 2000). St. John’s wort (a common nutraceutical used for
depression in humans) decreases the bioavailability of cyclosporine and digoxin,
probably through induction of P-gp and CYP3A by the flavonoids, hyperforin andhypericin (Mueller et al. 2004, Zhou et al. 2004). The potential outcome of these
P-gp and CYP3A interactions may be complex in herbivores that consume plants
with myriad PSMs.

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Many propose that PSMs are detoxified by microbes in foregut fermenting herbivores (e.g., ruminants, kangaroos, hoatzin). The
diverse microbial populations in the foregut can perform many reactions, which
can both reduce and increase the toxicity of ingested PSMs (Duncan et al. 2000,
Foley et al. 1999). However, there remain too few examples to judge whether
foregut microbial detoxification is an important driver of diet diversificationin wild herbivores. The best example comes from agricultural systems where
Jones & Megarrity (1986) showed that acquisition of a specific microorganism(Synergistes jonesii; Allison et al. 1992) enabled goats to consume greater quantities of Leucaena leucocephala containing mimosine, a toxic nonprotein aminoacid. Nonetheless, agriculturalists are focusing on identifying and manipulating
the microbial population of the foregut of sheep and cattle to degrade PSMs because they realize that breeding programs to eliminate PSMs from forage plants
can be counter-productive (McSweeney et al. 2002).
Several recent studies (Jones et al. 2000, 2001) conclude that microbial populations from wild browsers had no greater ability to degrade tanniniferous foods than
did those from domesticated cattle. This coupled with the reluctance of authorities
to allow the release of genetically modified microorganisms to degrade toxic compounds (Gregg et al. 1998) suggests that enhancement of microbial detoxification
is more likely to come from manipulating rumen populations rather than discovering new, highly specific organisms. In contrast, recent studies (Krause et al. 2004)
have started to use community genome approaches to identify specific changes in
the rumen microbiology of sheep eating tannin-rich forages, and ecologists should
see rapid progress in understanding the extent of microbial response to PSM-richdiets (at least in agricultural systems) over the next few years.

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MICROBIAL DETOXIFICATION

Regulation of PSM Intake
Browsing mammals encounter a diverse range of PSMs in the majority of the foods
they consume. Therefore, complete avoidance of PSMs in the diet is not likely to
be a realistic strategy, as animals would need to exclude most available plants fromtheir diet. The vast majority of PSMs that animals ingest are not so acutely toxic thata single bite would be lethal or severely detrimental, but large amounts of even lowpotency compounds can be harmful. Consequently, animals must have mechanismsthat allow them to detect and regulate their intake of PSMs to ensure that lowpotency toxins do not cause damage. Understanding the sorts of mechanisms thatanimals use to regulate toxin intake is vital if we are to integrate the effects of PSMs
with broader theories of feeding. For example, is the regulation of PSM intake partof the same mechanisms that animals use to recognize nutrient deficiencies or are
there separate regulatory mechanisms imposed on normal feeding patterns? Byunderstanding the interactions and tradeoffs between the intake of nutrients andPSMs, we can identify general patterns so that each new compound studied does
not have to be treated as a special case. Below we review evidence that animals
regulate PSM intake and describe potential mechanisms permitting regulation.

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The evidence that the intake of PSMs is regulated comes largely from dose response studies in which purified PSMs are
fed across a range of concentrations (5 to 10 times range) to captive animals.
For example, both common ringtail (Pseudocheirus peregrinus) and brushtail(Trichosurus vulpecula) possums adjusted food intake on diets containing different
concentrations of jensenone such that there was no difference in the daily intake ofjensenone. Ruffed grouse (Bonasa umbellus) also regulate their intake of coniferylbenzoate (CB) over a fivefold range of dietary concentrations (Jakubas et al. 1993).
However, it is worth noting that regulation does not appear to be as precise when
animals feed on natural plant diets containing the same compounds. We present
three mechanisms that we think animals may use to regulate their intake of PSMs.

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EVIDENCE OF REGULATED INTAKE

Conditioned
food aversions (CFAs) have long been known to be powerful influences on the dietsof herbivores (Provenza et al. 1998). CFAs arise when an animal makes an association between the taste or smell of a plant and some negative consequence—usually
illness. Provenza and coworkers (e.g., Provenza et al. 2003) have been instrumental in demonstrating that CFAs influence diet choices of large domestic animals
such as sheep, goats, and cattle and that CFAs are a useful practical method ofprotecting free-ranging livestock from being poisoned. In Provenza’s view, CFAs
are balanced by the possibility of animals forming conditioned preferences—they
associate the flavor of food with positive consequences such as enhanced energy
or protein status (Provenza et al. 1998).
In spite of the large volume of laboratory data that support a central role for
CFAs in herbivore foraging, there are several caveats to consider. First, there havebeen few direct demonstrations that the attenuation of nauseous sensations allows
herbivores to increase consumption. Lawler et al. (1998) showed that administration of the drug ondansetron [a specific serotonin (5HT3 ) receptor antagonist
that reduces nausea and vomiting in humans] led to greater intakes of the PSM
jensenone in two herbivorous marsupials and attributed the effect to reduction innauseous sensations. Similarly sheep consumed more endophyte-infected fescue
when dosed with a dopamine receptor antagonist that reduces nausea and vomitingin humans (Aldrich et al. 1993).
Second, there have been few demonstrations of CFAs where both the compounds responsible for the distinctive taste of the plant and the nausea-inducing
factors are naturally present in the same plant; nearly all studies rely on using theartificial agent LiCl to induce nausea. In contrast, Lawler et al. (1998) demonstrated
an ecologically relevant example in Eucalyptus where the concentrations of thedominant Eucalyptus terpene, 1,8-cineole, covaried with the concentrations of anausea-inducing agent jensenone. More examples like this would build confidence
in the ecological relevance of CFAs.
Finally, the ability of animals to form CFAs to PSMs must be tested underthe more complex foraging scenarios commonly experienced by free-ranging animals. For example, Duncan & Young (2002) showed that the ability of animals to

NAUSEOUS FEEDBACK CAUSING CONDITIONED FOOD AVERSIONS

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make associations between illness and a particular food were reduced when all test
foods were offered during the learning period, as would be the case in free-ranging
animals. Caution is prescribed in extrapolating results of simple conditioning experiments carried out with captive animals to free-ranging herbivores (Duncan &Young 2002).
Many studies
have demonstrated that foods can be repellent to herbivores without inducing
CFAs. Humans experience this when eating foods containing hot peppers. The
vanilloid compound in the peppers, capsaicin, irritates trigeminal nerves in themouth, generating a burning sensation and, if it is too intense, food consumption
is reduced. However, the experience rarely leads to aversion to such dishes in the
future. Similarly, it is clear that animals can use trigeminal feedback to regulate
their intakes of these irritant PSMs. For example, Jakubas et al. (1993) showedthat CB was a trigeminal irritant in birds and that ruffed grouse could regulate theirintake of CB in aspen.
Compounds that are bitter, but not necessarily irritant, may also be effective
deterrents at high concentrations and lead to thresholds in the ingestion of thePSM. For example, the intensely bitter phenolic glycoside, salicin, is an effective
antifeedant in willows (Salix sp.) for common brushtail possums in the field. However, the effect was due to “taste” rather than postingestive effects because direct
infusion of salicin into the stomach had no effect on subsequent salicin intake (Pass& Foley 2000).
Recent studies confirm that molecular differences in the vanilloid receptor between birds and mammals may explain why mammals but not birds are repelled
by a hot, peppery taste (Jordt & Julius 2002). In contrast, bitter substances are
significantly more repellent to birds. Recent advances in understanding the molecular basis of bitter tastes (e.g., Margolskee 2002) offer exciting opportunities tounderstand why some animals are more repelled by bitter compounds than others and to learn how the taste of PSMs integrates with other food components.
The differences between mammals and birds in their susceptibility to different
repellent PSMs is of particular interest in understanding the role of PSMs in fruit
dispersal, particularly the possibility of directed dispersal of fruits by either birds
or mammals (Cipollini & Levey 1997a, Tewksbury & Nabhan 2001).

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PRE-INGESTIVE EFFECTS: TASTE AND TRIGEMINAL STIMULATION

Recent experiments show that limits to the rate of detoxication of ingested PSMs can constrain feeding rates ofmammalian herbivores. However, it remains unclear how animals translate physiological effects into changes in feeding behavior. For example, brushtail possums
fed diets rich in benzoic acid ate more when provided with supplemental glycine
because the rate of formation of the detoxified excretory product benzoyl glycine(hippuric acid) was enhanced (Marsh et al. 2005). Animals recognized whether
diets contained supplemental glycine and modified their feeding accordingly. However, feeding rates did not change when brushtails were dosed with ondansetron

FEEDBACK FROM DETOXICATION LIMITATIONS

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GBC/OJODEARING  FOLEY  MCLEAN(Marsh et al. 2005), suggesting that nauseous feedback was not responsible for thechanges in food intake induced by dietary benzoate.

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Biotransformation
PSMs can be eliminated from the body by excretion or chemical change (biotransformation), or a combination of these processes. Because of the way the terrestrial
kidney works to conserve water, lipophilic substances are poorly excreted. In the
mammalian kidney, the plasma filtered at the glomerulus is nearly completely reabsorbed from the renal tubules, and lipophilic substances are extensively reabsorbed
across the renal tubular epithelium leaving polar molecules that cannot permeate
the epithelial cells to be excreted in the urine. The most lipophilic PSMs (e.g.,monoterpenes) are not excreted without transformation (Boyle et al. 1999, 2000a),whereas more polar PSMs (e.g., quercetin, gallic acid) are excreted unchanged tovarying extents (Schwedhelm et al. 2003, Wiggins et al. 2003).
Terrestrial animals have evolved a powerful suite of biotransformation enzymes
to convert lipophilic PSMs into more polar metabolites readily excreted in urine orbile. These biotransformation enzymes are broadly categorized into two groups:
functionalization (also called Phase 1), in which functional groups are introduced
into metabolites, and conjugation (Phase 2), in which adducts are formed withendogenous compounds to further increase polarity. Functionalization and conjugation enzymes can work alone or in tandem, depending on the substrate. The
most important are the mixed-function oxidases of the cytochrome P450 family(P450s) (Gonzalez & Nebert 1990, Guengerich 2004). These enzymes are considered to have evolved in part as a response to dietary plant toxins (Gonzalez &Gelboin 1994, Gonzalez & Nebert 1990). Although most drugs lose their activity
after biotransformation, there are examples of PSMs whose toxicity is mediatedby metabolites.
The most common functionalization reactions are oxidations by P450s, although other reactions (reduction, hydrolysis) can be important,depending on the chemical structure of the PSM. P450s are a large family of enzymes with different but overlapping substrate specificities and a common mechanism of action (Guengerich 2004). They are located in the smooth endoplasmic
reticulum where the membrane phospholipid provides an environment suitable
for their activity. The liver is the major organ for P450 activity but extrahepatic
sites, especially the gastrointestinal tract, are also important (Ding & Kaminsky2003). P450s have a general requirement for molecular oxygen, NADPH, andcytochrome P450 reductase, and the reaction results in the introduction of an oxygen atom in the form R-H to ROH. The oxidized metabolites may be similar tothe parent molecule, e.g., alcohols and acids formed from hydrocarbons such as
monoterpenes (Boyle 2000b, Boyle et al. 1999) or may become unrecognizable
through cleavage of the carbon skeleton (e.g., phenols and hydroxy acids formed
from complex phenolics such as tannins and flavonoids) (Schwedhelm et al. 2003,

FUNCTIONALIZATION

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Zhou et al. 2003). Analysis of the literature on human P450s with substrates andinhibitors reveals that there are five primary P450s for drug metabolism (CYP:
2D6, 3A4, 2C, 1A2, 2B6) and four for other substances such as PSMs (CYP: 1A1,
1B1, 2E1, 2A6; Rendic 2002). Comparison of P450s from humans and the puffer
fish (Takifugu rubripes) indicates that the overall pattern of P450 genes has been
well conserved for 420 million years (Nelson 2003).
Despite the general conservation of P450 genes, the activities of P450 enzymes
can vary widely between and within species due to differences in allelic forms
and expression (Gonzalez & Kimura 2003, Guengerich 2002, Wilkinson 2004).
For example, specialist marsupial folivores, whose diets are high in monoterpenes,
are able to more extensively oxidize monoterpenes than generalist folivores (Boyle
2000a; Boyle et al. 1999, 2000b, 2001). In vitro, the P450s from marsupial folivores
have greater activity in oxidizing terpenes compared to rat or human P450s (Passet al. 2001, 2002).
Metabolism does not always detoxify PSMs as many adverse reactions are dueto the formation of reactive and toxic metabolites (Gonzalez & Gelboin 1994). For
example, the pyrrolizidine alkaloids (Fu et al. 2004) and aflatoxin B1 form toxic
intermediates after biotransformation.
Conjugation reactions involve the addition of an endogenous molecule directly to a PSM or a metabolite formed from a functionalization reaction.
The most common conjugates are glucuronides and sulfates but glutathione may
also be an important conjugate. These conjugates bind to PSMs forming highlypolar products that are readily excreted in urine or bile (Shipkova et al. 2003),
although they require active transport to leave the cell (Konig et al. 1999). Conjugation is more energetically costly compared with functionalization in that an
endogenous compound, the conjugate, is typically excreted from the body as partof the process.
Conjugation with glucuronides occurs through any of ∼50 enzymes in the mammalian superfamily of UDP-glucuronosyltransferases (UGTs). These enzymes catalyze reactions between activated UDP-glucuronic acid and the -COOH, -OH and-NH2 groups of a vast array of endogenous and exogenous substrates such as
steroid hormones and the phenolic metabolites of flavonoids and tannins (Miners
et al. 2004, Radominska-Pandya et al. 1999). UGTs are located in the endoplasmic
reticulum of liver, gut, and kidney, and substrates must be lipophilic to reach themembrane-bound enzyme. This is demonstrated by the differential glucuronidationof terpene metabolites in marsupial folivores, in which the less polar hydroxyterpenes are extensively conjugated, whereas the more polar hydroxyacid metabolites
are excreted in the free form (Boyle et al. 1999, 2000).
The different forms of UGTs are proposed to have evolved in part in response to
the challenge of dietary PSMs (Bock 2003). There are marked species differencesin the pattern and rate of glucuronidation (Walton et al. 2001). Interestingly, the cat
and related carnivores are deficient in UGT activity and are highly sensitive to toxicity of certain nondietary UGT substrates such as acetaminophen and morphine

CONJUGATION

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GBC/OJODEARING  FOLEY  MCLEAN(Court & Greenblatt 2000). In the koala (Phascolarctos cinereus), which specializes on Eucalyptus, there is negligible conjugation of terpene metabolites, whichinstead are extensively oxidized to enable their excretion (Boyle et al. 2000a, 2001).
However, the koala does glucuronidate phenolic metabolites (McLean et al. 2003),
possibly because they are not readily oxidized by P450 enzymes.
Conjugation reactions with sulfate are similarly catalyzed by a large family ofcytosolic sulfotransferase enzymes (SULTs) that act on a vast array of endogenousand exogenous substrates, including phenols, benzylic alcohols, and hydroxylamines (Blanchard et al. 2004, Glatt & Meinl 2004, Kauffman 2004). The sulfonate group (SO3 − ) is transferred from 3 -phosphoadenosine 5 -phosphosulfate(PAPS) and forms a sulfate ester (SO4 ) only if the acceptor is an OH group. Phenols (e.g., gallic acid) can form both sulfate and glucuronide conjugates (Yasuda
et al. 2000). The proportions vary depending on the relative activities of the transferases and their cofactors (Glatt & Meinl 2004) as well as on species and dose.
For example, the rabbit excretes paracetamol mainly as glucuronides, whereas therat mainly excretes sulfates at low doses and glucuronides at high doses (Walton
et al. 2001).
Glutathione (GSH) forms conjugates with electrophilic toxins, which otherwise
could form adducts with nucleophilic sites on proteins and DNA leading to toxicity(Armstrong 1997, Eaton & Bammler 1999). The resulting glutathione conjugatesare either excreted in bile or undergo further metabolism to mercapturic acids,
which are excreted in urine. Some PSMs (e.g., formylphloroglucinols; McLean
et al. 2004) bind GSH rapidly, but others (e.g., isothiocyanates from glucosinolates;
Mithen et al. 2000) need catalysis by glutathione S-transferases (GSTs). There areseveral GST forms that occur both in the cytoplasm for soluble electrophiles andmembranes for more lipophilic substrates (Armstrong 1997, Eaton & Bammler
1999).
Because of the serious consequences of genotoxicity, where a single molecular hit can potentially result in mutation or cancer, it is perhaps significant that
there is a large overcapacity of GSH conjugating activity, both in GSH and GST
concentrations (Rinaldi et al. 2002). This system protects cells from endogenous
electrophiles (e.g., the fatty acid oxidation product, 4-hydroxy-2-nonenal) andPSMs (e.g., aflatoxin). PSMs can alter GST activity by inhibition (e.g., curcumin)
and induction (e.g., isothiocyanates, goitrin; Eaton & Bammler 1999). The wide
species differences in susceptibility to aflatoxin B1 , a secondary metabolite produced by some strains of Aspergillus, is due to variations in the relative activitiesof metabolic activation to the electrophilic aflatoxin B1 -8,9-epoxide and its detoxification by GST (Klein et al. 2000).
Although conjugation is usually considered to be a detoxifying reaction, withsome substrates the glucuronide or sulfate can generate a reactive electrophile that
forms adducts with proteins and DNA resulting in toxicity to the cell or genome.
Examples of reactive conjugates of PSMs are the acyl glucuronide of salicylic
acid (Spahn-Langguth & Benet 1992) and the sulfate ester of safrole (Kauffman2004).

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The activity of enzymes and transporters can be modified by PSMs that inhibit their function or stimulate the synthesis of more active protein (a process called “induction”), or both effects insuccession (Hollenberg 2002). Inhibition can be due to competition between substrates for limited enzyme or an irreversible “mechanism-based” reaction where
the inhibitor is oxidized by the P450 to a reactive metabolite that binds covalently
to the active site of the enzyme. One example of a mechanism-based inhibitor is6 , 7 -dihydroxybergamottin, a PSM in grapefruit juice that destroys CYP3A inenterocytes, requiring three days for recovery of enzyme activity (Greenblatt et al.
2003).
Induction of P450 enzymes occurs via several nuclear receptors. The nuclear
receptors activate target genes in a similar manner to the steroid hormone receptors (Wang & LeCluyse 2003). Polycyclic aromatic hydrocarbons and dietary
constituents were the first substances found to induce metabolism, and now many
drugs and natural products are recognized as inducing agents (Harris et al. 2003,
Hollenberg 2002).
Conjugation enzymes are inducible as well as subject to inhibition. PSMs suchas hyperforin, β-napthoflavone and indole-3-carbinol induce UGTs as well as
CYPs via the nuclear receptors AhR, PXR, and CAR (Bock & Kohle 2004). Induction of sulfonation is not as marked (Coughtrie & Johnston 2001) but glutathionetransferases are upregulated by their electrophilic substrates (Rinaldi et al. 2002).
Sulfonation is potently inhibited by the polyphenols quercetin, epigallocatechin
and epicatechin (Antonio et al. 2003). Glucuronidation and glutathione conjugation do not seem to be as subject to inhibition by PSMs (Eaton & Bammler 1999,
Radominska-Pandya et al. 1999), although glutathione conjugates with hydrophobic substituents (e.g., isothiocyanates) bind and inhibit the active site of GSTs
(Armstrong 1997).
Because of the multiplicity of enzyme forms, PSMs do not uniformly induce orinhibit all functionalization and conjugation enzymes (Manson et al. 1997). PSMs
can have complex effects on P450 regulation, depending on the substances andamounts consumed, target organ, and species (Zhou et al. 2003). There is also large
individual variability in the inhibition and induction of P450 enzymes (Lin & Lu2001) and polymorphism in transporters (Ieiri et al. 2004). The consequences forherbivores eating large amounts of PSMs that can act as inhibitors of metabolism(during the feeding session) and inducers (on the following days) will be complex
interactions.

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INDUCTION AND INHIBITION OF METABOLISMHERBIVORES AND PSMs
Below we give an overview of recent research on how PSMs influence diet selectionin the major groups of terrestrial herbivores, e.g., the lizards, birds, and mammals.
Some groups such as the lizards have received relatively little attention in this area
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precludes reasonable speculation regarding the relative importance of PSMs to
one group versus another. Clearly more research is necessary with respect to thecomparative physiology of biotransformation mechanisms used by each groupprior to the establishment of generalizations.

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Lizards
Herbivory is relatively rare in lizards; only 3% of all species are herbivorous (120species; Cooper & Vitt 2002). The diets of several herbivorous lizards are documented and several are known to eat or avoid plants with notable PSMs. For
example, the chuckwalla (Sauromalus obesus) preferentially feeds on the flowersof creosote bush (Larrera tridentata) while avoiding the resinous leaves that contain high levels of toxins (Nagy 1973). Despite extensive documentation on dietselection by lizards, there are very few studies that examine the role that PSMs
play in food choice.
Of the herbivorous lizards, those that have received the most attention withrespect to the role that PSMs play in diet selection are the herbivorous whiptail lizards of the southern Caribbean, Cnemidophorus murinus and C. arubensis.
Studies on both species revealed that whiptails avoided some PSMs such as tannins and alkaloids, but were less deterred by other PSMs such as cyanide (Dearing& Schall 1992, Schall & Ressel 1991). Furthermore cyanide was ingested at extremely high doses with no apparent effect (Schall & Ressel 1991). Caribbean
whiptails are capable of discriminating plant odors from those of nonfood items(Cooper et al. 2002). The ability to detect plant chemical cues in whiptails aswell as other herbivorous lizards appears to be a trait that evolved with herbivory(Cooper 2003). Herbivorous whiptails can detect differences in concentrations of
PSMs, e.g., quinine. The acceptable concentration of quinine in experimental foodvaried seasonally and may be a function of the availability of other less toxic foods(Schall 1990). These studies indicate that PSMs influence diet selection and thatherbivorous whiptails have physiological capabilities for detecting PSMs. Given
that these two species of Cnemidophorus are not considered to be as specialized
for herbivory as some of the iguanans, it is likely that the more specialized lizards
also possess such traits and may have other novel traits for detecting and dealing
with PSMs.
Little is known about the detoxification mechanisms that herbivorous lizards
employ in processing toxins. Obviously, much more research is needed on how
PSMs influence diet selection in herbivorous lizards.

Birds
Herbivory is also rare among birds, presumably due to mass tradeoffs associatedwith flight. However, there are a number of herbivorous birds such as geese, grouse,some parrots, and the hoatzin (Opisthocomus hoazin) that feed on terrestrial plants.
PSMs play a significant role in diet selection of herbivorous bird species. The
hoatzin, for example, is a folivore that inhabits riparian areas of South America.

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Although selective in its diet, many of the plants consumed by the hoatzin contain
PSMs (Dominguez-Bello et al. 1994). The hoatzin’s ability to detoxify certain
PSMs may be a consequence of foregut fermentation rather than biotransformation
by its own enzymes. The hoatzin has an atypically enlarged crop to house symbiotic
bacteria that ferment fiber. It has been proposed that these bacteria in the crop
biotransform PSMs before they reach the absorptive tissue in the small intestine(Grajal et al. 1989); however, this has not yet been directly tested. Furthermore,
the spectrum of compounds that these fermentative bacteria can process may belimited to alkaloids rather than tannins (Jones & Palmer 2000). Diet selectionof the hoatzin is consistent with this hypothesis in that it tends to avoid tanninrich forages and selects young leaves, which typically are defended by PSMs likealkaloids.
The ruffed grouse has likely received the most attention with respect to detoxification of PSMs. Ruffed grouse consume aspen flowers (Populus tremuloides) as
well as leaves from a variety of evergreen shrubs and ferns. CB, a phenylpropanoid
ester present in aspen, is a primary determinant of feeding (Jakubas et al. 1989).
Grouse can detect CB concentration differences and feed selectively on flowers
low in CB. Detoxification of CB by grouse occurs through some functionalization reactions but also extensively via conjugation with both glucuronic acid andornithine (Jakubas et al. 1993). The energetic cost of detoxification of aspen flowers with low levels of CB, typical of that consumed by grouse in the field, wasenormous. Grouse lost 10% of metabolizable energy (e.g., energy not lost in urine
or feces) in simply the detoxification conjugates (glucuronic acid and ornithine)
excreted. This cost is an underestimate of the total energy used in detoxification as
it does not account for energy used in enzymatic reactions that attach the conjugate
to the PSM or functionalization reactions. Furthermore, losses of the amino acid,ornithine, as a conjugate increased the minimum nitrogen requirement. Anotherstudy on grouse consuming leaves from several different species of shrubs and atdifferent doses revealed that usage of conjugation pathways varies among plant
species but also within species at different doses (Hewitt & Kirkpatrick 1997).
Surprisingly, the shift in pathway usage within a particular food type does notappear to be related to a limitation of conjugates or saturation of the detoxification
pathway (Hewitt & Kirkpatrick 1997).
PSMs are not thought to play a large role in diet selection by geese (but see
Buchsbaum et al. 1984), in contrast to grouse and the hoatzin (Sedinger 1997). A
possible cause of this disparity is that geese feed primarily on monocots, which
are typically low in PSMs, compared to the dicots high in PSMs fed on by grouse
and the hoatzin. Furthermore, monocot feeders are often believed to have lower
capacities for detoxification. However, comparisons of detoxification capacities
have not been conducted in herbivorous species of birds.
PSMs are thought to be instrumental in fruit selection by frugivorous birds.
Because frugivores are not the subject of this review, we direct readers to a few
recent works as an introduction into this active and controversial area of research(e.g., Cipollini & Levey 1997a, 1997b; Tewksbury & Nabhan 2001).

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Mammals
Herbivory is widespread among mammals, which may in part account for thegreater number of studies on mammals compared to lizards and birds. In thepast 30 years, numerous studies have demonstrated that PSMs play a significant
role in diet selection of mammalian herbivores (e.g., Berger et al. 1977, Foley
et al. 1999, Reichardt et al. 1990). Furthermore, detoxification is expensive andcomparable to the cost of reproduction in many mammals (Sorensen et al. 2005a).
Because there have been far more studies on mammals than lizards or birds, below
we synthesize what has been learned in general rather than profiling individual
species of mammalian herbivores.
Studies of the role of PSMs on mammalian foraging have been largely influenced by Freeland & Janzen’s seminal paper (Freeland & Janzen 1974). In thiswork, they wedded data from pharmacological studies on laboratory rodents toecological studies on wild herbivores to produce theory predicting the foraging
behavior of herbivores with respect to PSMs. One of their main points explained
the paucity of dietary specialization among mammalian herbivores. They suggested that the default state of the mammalian biotransformation system promoted
a generalist foraging strategy because this system can process limited quantitiesof myriad xenobiotics through numerous detoxification pathways. Such a system
would force mammals to be generalist feeders to prevent exceeding the capacity of
any one of the pathways. A few experimental studies support this hypothesis; herbivores eat more when offered plants with differing PSMs and process the PSMs
through different pathways. Unfortunately, all the studies to date in this area havebeen on a single mammalian herbivore, the brushtail possum (reviewed in Marshet al. 2005). Studies on other species are needed to evaluate whether limitationsof the detoxification system explain the preponderance of dietary generalizationin mammalian herbivores.
A recent hypothesis that has emerged from studies of various mammalian herbivores is that specialists use detoxification pathways that are energetically lessexpensive than generalist feeders. Specifically, specialists appear to rely moreon functionalization pathways than on energetically costly conjugation pathways(Boyle et al. 2000a, 2001; Lamb et al. 2004). As functionalization pathways may
have greater substrate specificity than conjugation pathways, a potential tradeoff of specialization may be the inability to process novel toxins. Sorensen et al.
(2005b) demonstrated such a tradeoff in the juniper specialist, Neotoma stephensi,
on a novel toxin. Clearly more work on other species and PSMs is necessary to
determine the generality of this tradeoff.

TOOLS FOR FUTURE RESEARCH
There is still much to understand about how PSMs mediate diet selection in terrestrial herbivores. In general, we understand little of the mechanisms used bywild herbivores and how these mechanisms provide feedback to influence diet

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selection. Rigorously addressing large-scale ecological or evolutionary questions
requires more detail on the underlying physiological mechanisms. Below we describe two approaches that will be fruitful for future studies in plant–mammalinteractions.

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Genomics
The burgeoning field of genomics offers a number of tools to address the role of
PSMs in nutritional ecology. The detoxification limitations hypothesis of Freeland& Janzen (Freeland & Janzen 1974) may soon be testable at the level of entire
detoxification systems through the use of microarray technology. A single microarray measures gene expression of thousands of genes simultaneously. Commercial
arrays profiling the detoxification system have been constructed for toxicology
studies in laboratory rats, and microarrays produced for one species have beensuccessfully used for other species (Moody et al. 2002). Thus, it may be possible to use the rat toxicology microarrays on nonmodel herbivore systems such asvoles or woodrats. As the technology develops, so will the possibility and affordability of making arrays for herbivores of interest. In addition to microarrays, therapidly growing numbers of sequencing projects facilitate studies on the evolutionof detoxification genes. Questions such as how do functionalization genes change
at the molecular level in specialists compared to generalists can be addressed ona large scale using a combination of database mining (e.g., GenBank) and lab
work.

Standardized Functional Assays
Studies of the capacity of herbivores to eliminate dietary PSMs would be greatly
assisted if we could readily measure the activity of elimination processes suchas enzymes, transporters, and renal excretion. The elimination of probe drugs isused in pharmacokinetic studies, but these tests typically require procedures suchas intravenous administration, serial blood sampling, and the measurement of theconcentrations of drugs and their metabolites (Pelkonen 2002). These methodological complications can be avoided by using a pharmacological response suchas time sleeping under anesthesia as a surrogate measure of biotransformation
capability. Usually this has been done in comparative studies, such as the effectof capsaicin on hexobarbitone sleeping time (Hamid et al. 1985) and the effect of
7,8-benzoflavone on zoxazolamine paralysis.

ACKNOWLEDGMENTS
We thank Michele Skopec, Shannon Haley, Ann-Marie Torregrossa, and Ben
Moore for comments on this manuscript. Our work was supported by NSF (IBN
0236402 to MMD) and the Australian Research Council (to WJF and SM). We
thank Kathy Smith for assistance with manuscript preparation.

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The Annual Review of Ecology, Evolution, and Systematics is online at
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Annual Review of Ecology, Evolution, and Systematics
Volume 36, 2005

CONTENTSTHE GENETICS AND EVOLUTION OF FLUCTUATING ASYMMETRY,${journal.abbrev} 2005.36:169-189. Downloaded from arjournals.annualreviews.org
by AUSTRALIAN NATIONAL UNIVERSITY on 11/14/05. For personal use only.

Larry J. Leamy and Christian Peter Klingenberg

LIFE-HISTORY EVOLUTION IN REPTILES, Richard Shine
THE EVOLUTIONARY ENIGMA OF MIXED MATING SYSTEMS IN PLANTS:
OCCURRENCE, THEORETICAL EXPLANATIONS, AND EMPIRICAL
EVIDENCE, Carol Goodwillie, Susan Kalisz, and Christopher G. Eckert
INDIRECT INTERACTION WEBS: HERBIVORE-INDUCED EFFECTS
THROUGH TRAIT CHANGE IN PLANTS, Takayuki Ohgushi
EVOLUTIONARY HISTORY OF POALES, H. Peter Linder and Paula J. Rudall
THE EVOLUTION OF POLYANDRY: SPERM COMPETITION, SPERM
SELECTION, AND OFFSPRING VIABILITY, Leigh W. Simmons
INDIVIDUAL-BASED MODELING OF ECOLOGICAL AND EVOLUTIONARY
PROCESSES, Donald L. DeAngelis and Wolf M. Mooij
THE INFLUENCE OF PLANT SECONDARY METABOLITES ON THE
NUTRITIONAL ECOLOGY OF HERBIVOROUS TERRESTRIAL
VERTEBRATES, M. Denise Dearing, William J. Foley, and Stuart McLean
BIODIVERSITY AND LITTER DECOMPOSITION IN TERRESTRIALECOSYSTEMS, Stephan Hättenschwiler, Alexei V. Tiunov, and Stefan Scheu
THE FUNCTIONAL SIGNIFICANCE OF RIBOSOMAL (R)DNA VARIATION:
IMPACTS ON THE EVOLUTIONARY ECOLOGY OF ORGANISMS,
Lawrence J. Weider, James J. Elser, Teresa J. Crease, Mariana Mateos,
James B. Cotner, and Therese A. Markow

EVOLUTIONARY ECOLOGY OF PLANT ADAPTATION TO SERPENTINESOILS, Kristy U. Brady, Arthur R. Kruckeberg, and H.D. Bradshaw Jr.
BIODIVERSITY-ECOSYSTEM FUNCTION RESEARCH: IS IT RELEVANT TOCONSERVATION? Diane S. Srivastava and Mark Vellend
CONSEQUENCES OF THE CRETACEOUS/PALEOGENE MASS EXTINCTION
FOR MARINE ECOSYSTEMS, Steven D’Hondt
LANDSCAPE ECOLOGY: WHAT IS THE STATE OF THE SCIENCE?
Monica G. Turner

1
23

47
81
107
125
147

169
191

219
243
267
295
319

ECOLOGY AND EVOLUTION OF APHID-ANT INTERACTIONS,
Bernhard Stadler and Anthony F.G. Dixon

345v

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CONTENTSEVOLUTIONARY CAUSES AND CONSEQUENCES OFIMMUNOPATHOLOGY, Andrea L. Graham, Judith E. Allen,
and Andrew F. Read

THE EVOLUTIONARY ECOLOGY OF GYNOGENESIS, Ingo Schlupp
MEASUREMENT OF INTERACTION STRENGTH IN NATURE,
J. Timothy Wootton and Mark Emmerson${journal.abbrev} 2005.36:169-189. Downloaded from arjournals.annualreviews.org
by AUSTRALIAN NATIONAL UNIVERSITY on 11/14/05. For personal use only.

MODEL SELECTION IN PHYLOGENETICS, Jack Sullivan and Paul Joyce
POLLEN LIMITATION OF PLANT REPRODUCTION: PATTERN AND
PROCESS, Tiffany M. Knight, Janette A. Steets, Jana C. Vamosi,
Susan J. Mazer, Martin Burd, Diane R. Campbell, Michele R. Dudash,Mark O. Johnston, Randall J. Mitchell, and Tia-Lynn Ashman

373
399
419
445

467

EVOLVING THE PSYCHOLOGICAL MECHANISMS FOR COOPERATION,
Jeffrey R. Stevens, Fiery A. Cushman, and Marc D. Hauser

NICHE CONSERVATISM: INTEGRATING EVOLUTION, ECOLOGY, AND
CONSERVATION BIOLOGY, John J. Wiens and Catherine H. Graham
PHYLOGENOMICS, Hervé Philippe, Frédéric Delsuc, Henner Brinkmann,and Nicolas Lartillot

499
519
541

THE EVOLUTION OF AGRICULTURE IN INSECTS, Ulrich G. Mueller,
Nicole M. Gerardo, Duur K. Aanen, Diana L. Six, and Ted R. Schultz

INSECTS ON PLANTS: DIVERSITY OF HERBIVORE ASSEMBLAGESREVISITED, Thomas M. Lewinsohn, Vojtech Novotny, and Yves Basset
THE POPULATION BIOLOGY OF MITOCHONDRIAL DNA AND ITSPHYLOGENETIC IMPLICATIONS, J. William O. Ballard and David M. Rand
INTRODUCTION OF NON-NATIVE OYSTERS: ECOSYSTEM EFFECTS ANDRESTORATION IMPLICATIONS, Jennifer L. Ruesink, Hunter S. Lenihan,
Alan C. Trimble, Kimberly W. Heiman, Fiorenza Micheli, James E. Byers,
and Matthew C. Kay

563
597
621

643

INDEXES
Subject Index
Cumulative Index of Contributing Authors, Volumes 32–36
Cumulative Index of Chapter Titles, Volumes 32–36

ERRATA
An online log of corrections to Annual Review of Ecology,
Evolution, and Systematics chapters may be found at
http://ecolsys.annualreviews.org/errata.shtml

691
707
710