Perspectives in Biology and Medicine

PERSPECTIVES IN BIOLOGY AND MEDICINE Volume 24 · Number 1 ¦ Autumn 1980 HERBAL TEAS AND TOXINS: NOVEL ASPECTS OF PYRROLIZIDINE POISONING IN THE UNITED STATES RYANf. HUXTABLE* This article reviews the discovery of pyrrolizidine alkaloid poisoning in the United States caused by the drinking of herbal tea and describes some of the difficulties involved in establishing a causal relationship between exposure to these alkaloids and the delayed appearance of toxic symptoms. In addition, some ofthe more general problems presented by the widespread use of herbs in various forms are addressed. First, however , a brief overview is given of the toxicity of this class of alkaloids. Occurrence and Toxicity ofPyrrolizidine Alkaloids Pyrrolizidines occur in many plant families, including Boraginaceae, Compositae, Gramineae, Leguminosae, Orchidaceae, Rhizophoraceae, Santalaceae, and Saptoaceae. Part structures of these alkaloids are illustrated in figure 1. Toxic alkaloids contain an unsaturated ring. These alkaloids, and the plants in which they occur, are hepatotoxins, producing veno-occlusive disease, hepatomegaly and—with some alkaloids— liver cancers [I]. There is good evidence that the mechanism of toxicity involves a "lethal synthesis" in the liver whereby the alkaloids are metabolized to pyrroles (fig. 1). Pyrroles are chemically active and serve as biological alkylating agents by the mechanism shown in figure 2, in which groupsX The author thanks Charles Mason, Curator, University ofArizona Herbarium, for plant identifications. Laboratory work supported by USPHS grant HL-20087. ?Department of Pharmacology, Health Sciences Center, University of Arizona, Tucson, Arizona 85724.© 1980 by The University of Chicago. 003 1-5982/81/2401-0208$01.00 Perspectives in Biology and Medicine ¦ Autumn 1980 \ 1 and Y represent nucleophilic portions of proteins or nucleic acids, such as sulfhydryl groups [2]. Alkylation is a widespread mechanism of toxicity and takes place with many mutagens and carcinogens apart from pyrrolizidines. Human Exposure to Pyrrolizidine Alkaloids Pyrrolizidine alkaloid poisoning is a public health problem in many areas of the world. This is partly due to the wide botanical and geoHE PATOTOXlCNON-HEPAT0T0XIC PYRROLE Pyrrolizidine Part Structures Fig. 1.—Pyrrolizidine part structure. The omitted portion of the structure is usually a cyclic diester grouping (- CO.R.CO -). Toxic alkaloids are metabolized to N-oxides and pyrroles. The cyclic diester may also be metabolically hydrolyzed. PYRROLE TOXICITY 0 0 0 0> ilile li^ II' R -C-0} CH 0-C-R2X-v CH OC-R2X CH^tT-C-R2 eft' -U c& -U f \ X CH,X CH. Y Fig. 2.—Pyrrole toxicity. Pyrroles formed in the liver are postulated to be toxic because of their ability to alkylate nucleophilic groups, such as sulfhydryl (X,Y), on cell macromolecules . Based on a proposal of Mattocks [2]. 2 I Ryanf. Huxtable · Herbal Teas and Toxins graphical distribution of pyrrolizidine-containing plants. There are two major sources of human exposure: accidental contamination of foodstuffs and the deliberate use of pyrrolizidine-containing plants in herbal preparations. Accidental contamination falls into two categories: that of continuous low-level contamination that may last for many years and epidemic poisoning caused by occasional massive contamination of foodstuffs. Recent examples of the latter occurred both in Afghanistan and in India in 1976. These epidemics were caused by Heliotropium and Crotalaria species contaminating fields of wheat and being harvested along with the grain to make bread. Wheat from the affected area was found to contain about 300 mg of Heliotropium seeds per kilogram of wheat. The Afghanistan outbreak involved approximately 1 ,600 cases of veno-occlusive disease of the liver [3]. Many of these patients died. The true scope of the epidemic may have been much larger however, due to the fact that the outbreak occurred in a primitive area where health care is uncertain and hard to obtain. Furthermore, many exposed persons may have suffered long-term deleterious consequences that did not result in an immediate clinical picture. The Indian epidemic involved fewer people. However, of the 67 recorded cases, 28 died [4]. Chronic contamination of foodstuffs has been a problem in South Africa. Here the major offending species appear to be Senecio and Crotalaria, and the usual route of exposure is that of these plants contaminating grains used to prepare food [5]. Senecio poisoning by this route has been thought to be responsible for the...