This book succeeds Review of Medical Pharmacology , by Meyers, Jawetz, and Goldfien. Edited by B. G. Katzung, some of the important areas covered include drug receptors and pharmacodynamics, pharmacokinetics of absorption and biotransformation of drugs, autonomic pharmacology of cholinergic and adrenergic receptor stimulants and antagonists, antihypertensive agents, cardiac glycosides and other agents used in the treatment of congestive heart failure, therapeutic drugs for cardiac arrhythmias, diuretics, pharmacology of the CNS drugs such as anticonvulsants and anesthetics, antidepressants, narcotic analgesics, nonsteroidal anti-inflammatory agents, endocrine pharmacology, antimicrobial and antimycobacterial drugs, antiprotozoal and antihelmintic drugs, cancer chemotherapy, and drugs and the immune system. Written by several prominent researchers and scientists, each chapter begins with a section on the basic pharmacology, chemistry, pharmacokinetics, and pharmacodynamics of the agents under discussion. This is followed by a section on clinical pharmacology, which deals with relevant information regarding the clinical use of drugs on the various

Basic and Clinical Pharmacology

Tannins in plant-herbivore interactions.

'Summary'	733	
I.	'Introduction'	733	
II.	'PSM variation in time: ontogeny, phenology and induced defences'	734	
III.	'PSM variation through space: the role of environment'	735	
IV.	'Genes and biosynthetic pathways underlying PSM variation'	735	
V.	'Mechanisms for diversification of PSMs'	735	
VI.	'Examples of diversity from specific biosynthetic pathways'	737	
VII.	'How and why is chemical diversity maintained?'	739	
VIII.	'Evolvability of PSM variation'	740	
IX.	'Evolutionary strategies and diversity in plant chemical defence'	742	
X.	'Conclusions and future directions'	744	
 	'Acknowledgements'	745	
 	References	745	


Summary
Plant secondary metabolites (PSMs) are ubiquitous in plants and play many ecological roles. Each compound can vary in presence and/or quantity, and the composition of the mixture of chemicals can vary, such that chemodiversity can be partitioned within and among individuals. Plant ontogeny and environmental and genetic variation are recognized as sources of chemical variation, but recent advances in understanding the molecular basis of variation may allow the future deployment of isogenic mutants to test the specific adaptive function of variation in PSMs. An important consequence of high intraspecific variation is the capacity to evolve rapidly. It is becoming increasingly clear that trait variance linked to both macro- and micro-environmental variation can also evolve and may respond more strongly to selection than mean trait values. This research, which is in its infancy in plants, highlights what could be a missing piece of the picture of PSM evolution. PSM polymorphisms are probably maintained by multiple selective forces acting across many spatial and temporal scales, but convincing examples that recognize the diversity of plant population structures are rare. We describe how diversity can be inherently beneficial for plants and suggest fruitful avenues for future research to untangle the causes and consequences of intraspecific variation.

https://nph.onlinelibrary.wiley.com/doi/pdf/10.1111/nph.12526

Explaining intraspecific diversity in plant secondary metabolites in an ecological context.

Herbaceous vegetation under temperate climatic conditions generally shows nitrogen- or phosphorus-limited plant growth, which creates conditions for a high botanical diversity. Is nitrogen (N) or phosphorus (P) the most important limiting factor, or are both generally in short supply? What are the consequences of Increased N and P inputs that result from anthropogenic disturbances? A new indicator of N or P limitation, that is, the vegetation N:P ratio, allows us to address these questions for a range of mires, dune slacks and moist grasslands.

Nitrogen-or phosphorus-limited growth in herbaceous, wet vegetation : relations with atmospheric input and management regimes

▪ 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 with respect to PSMs. We also summarize recent findings of plant–animal interactions for lizards, birds, and mammals. Finally, we discuss some new tools that can be applied to long-standing questions of plant–vertebrate interactions.

/pdf/the-influence-of-plant-secondary-metabolites-on-the-1vf9dtqn1p.pdf

The Influence of Plant Secondary Metabolites on the Nutritional Ecology of Herbivorous Terrestrial Vertebrates

The detoxification limitation hypothesis is firmly entrenched in the literature to explain various aspects of the interaction between herbivores and plant toxins. These include explanations for the existence of specialist and generalist herbivores and for the prevalence of each of these. The hypothesis suggests that the ability of mammalian herbivores to eliminate plant secondary metabolites (PSMs) largely determines which plants, and how much, they can eat. The value of the hypothesis is that it provides a clear framework for understanding how plant toxins might limit diet breadth. Thus, it is surprising, given its popularity, that there are few studies that provide experimental support either for or against the detoxification limitation hypothesis. There are two likely reasons for this. First, Freeland and Janzen did not formally propose the hypothesis, although it is implicit in their paper. Second, it is a difficult hypothesis to test, requiring an understanding of the metabolic pathways that lead to toxin elimination. Recent attempts to test the hypothesis appear promising. Results suggest that herbivores can recognize mounting saturation of a detoxification pathway and adjust their feeding accordingly to avoid intoxication. One strategy they use is to ingest a food containing a toxin that is metabolized by a different pathway. This demonstrates that careful selection of food plants is a key to existing in a chemically complex environment. As more studies characterize the detoxification products of PSMs, we will better understand how widespread this phenomenon is.

The Detoxification Limitation Hypothesis: Where Did it Come From and Where is it Going?

Most herbivores eat more and survive better when they have access to a variety of foods. One explanation involves the detoxification of plant secondary metabolites (PSMs). By feeding from a variety of plants that contain different classes of PSMs, animals can use multiple detoxification pathways and presumably consume more food. Although popular, this theory is difficult to test because it requires knowledge of the detoxification pathways of each PSM in the diet. We established that common brushtail possums (Trichosurus vulpecula) use various combinations of oxidation, hydrolysis, and conjugation with glucuronic acid (GA) or glycine to detoxify six PSMs. Compared to their ingestion of a single PSM, possums ate more when offered a choice between two diets containing PSMs that require apparently independent detoxification pathways (benzoate and 1,8-cineole, benzoate and p-cymene, benzoate and orcinol, benzoate and salicin, or orcinol and 1,8-cineole). However, possums still did not eat as much of these diets as they did of a basal diet free of PSMs. This suggests that detoxification pathways are never independent, but are separated instead by degrees. In contrast, possums offered a choice of two PSMs that require competing detoxification pathways (1,8-cineole and p-cymene, 1,8-cineole and salicin, or orcinol and salicin) ate no more than when offered diets containing one of the compounds. There was an exception: even though both rutin and orcinol are detoxified via conjugation with GA, the feeding behavior of possums did not suggest competition for detoxification pathways. This implies that the supply of GA is not limiting. This study provides the first convincing evidence that herbivorous mammals can eat more by selecting mixed diets with a diversity of PSMs that make full use of their detoxification potential. It also emphasizes that other behavioral and physiological factors, such as transient food aversions, influence feeding behavior.

/pdf/conflicting-demands-on-detoxification-pathways-influence-how-145lt2091g.pdf

Conflicting demands on detoxification pathways influence how common brushtail possums choose their diets

The effect of two plant secondary metabolites, tannins and formylated phloroglucinol compounds (FPCs), on the intake of Eucalyptus foliage by common ringtail (Pseudocheirus peregrinus) and common brushtail possums (Trichosurus vulpecula) was studied. We manipulated the amount of tannin that was free to bind with protein by coating foliage with polyethylene glycol 4000 (PEG) and relied on natural intraspecific variation in FPC concentrations. In contrast to ringtail possums, brushtail possums showed a greater tolerance to FPCs and ate more foliage when it was coated with PEG, suggesting that tannins limited their food intake. Brushtails detected the effects of tannins through immediate oral sensations rather than through systemic effects. Ringtail possums appeared highly tolerant of foliar tannins yet susceptible to low concentrations of FPCs. We could not detect any interaction between tannins and FPCs that affected the intake of Eucalyptus foliage by either species of possum. Although ringtail and brushtail possums are widely regarded as specialist and generalist folivores, respectively, their differential susceptibility to co-occurring secondary metabolites suggests greater complexity. Each possum species appears to be a specialist in its own right, which leads to a partitioning of available foliage. Brushtails avoid tannins and ringtails avoid FPCs.

/pdf/differential-susceptibility-to-eucalyptus-secondary-40grmik08g.pdf

Differential susceptibility to Eucalyptus secondary compounds explains feeding by the common ringtail (Pseudocheirus peregrinus) and common brushtail possum (Trichosurus vulpecula)

The view that nutrition underpins the replacement and expansion of all animal populations is now widely accepted. However, there are relatively few examples in wild species that define the critical nutrients and critical periods of nutrient supply and even fewer examples that demonstrate a link between the conservation of vulnerable fauna and nutritional status. This is partly explained by the difficulties in measuring the food intake and diet composition of wild animals. Thus, there is little idea of the rates of intake of nutrients and of toxins – the key factors that define the nutritional status of animals. This, in turn, makes it difficult to predict how nutrition will affect populations. Consequently nutrition, although widely recognized and implicated in population dynamics, is rarely a discipline for managing and conserving populations.

/pdf/the-role-of-nutrition-in-the-conservation-of-the-marsupial-2wb9d8cb0m.pdf

The role of nutrition in the conservation of the marsupial folivores of eucalypt forests

A central theory in mammalian herbivore-plant interactions is that feeding decisions depend on an animal's capacity to detoxify plant secondary metabolites (PSMs). Thus, if a herbivore could detoxify a PSM faster, it might eat more. This theory has been difficult to test because the mechanisms by which herbivores detoxify most PSMs are largely unknown. We investigated whether common brushtail possums alter aspects of their feeding in response to an increased capacity to detoxify benzoic acid, a common PSM. Animals detoxify benzoic acid primarily by conjugating it with glycine to form benzoyl glycine (hippuric acid). Therefore, adding glycine to a diet that contains benzoic acid provides a simple way to study how detoxification constrains feeding in mammals. Brushtail possums offered supplementary glycine metabolized benzoate faster and, in response, ate more. Furthermore, when given a choice, brushtail possums selected a diet containing both ben- zoate and glycine over diets with a high concentration of just one of these supplements. The possums' aversion to glycine may explain why their ability to select a favorable diet combination from feeders containing diets with each of the supplements seemed less acute: they preferred diets containing benzoate alone over those containing glycine and did not mix their diet even though it would have allowed them to eat more benzoate and thus more food. Administering the anti-emetic drug, ondansetron (a specific 5-HT 3 receptor antago- nist), did not alter the amount eaten of diets containing benzoate, glycine, or both, suggesting that 5-HT3 receptors do not regulate benzoate or glycine intake. The results show that common brushtail possums recognize changes in their detoxification capacity and alter their feeding response accordingly.

/pdf/detoxification-rates-constrain-feeding-in-common-brushtail-21qrqmzr6n.pdf

Karen J. Marsh

Papers

The Detoxification Limitation Hypothesis: Where Did it Come From and Where is it Going?

Conflicting demands on detoxification pathways influence how common brushtail possums choose their diets

Differential susceptibility to Eucalyptus secondary compounds explains feeding by the common ringtail (Pseudocheirus peregrinus) and common brushtail possum (Trichosurus vulpecula)

The role of nutrition in the conservation of the marsupial folivores of eucalypt forests

Detoxification rates constrain feeding in common brushtail possums (trichosurus vulpecula)