4-Hydroxyphenylpyruvate dioxygenase (HPPD) inhibitors (HPPD inhibitors) are a class of herbicides that prevent growth in plants by blocking 4-Hydroxyphenylpyruvate dioxygenase, an enzyme in plants that breaks down the amino acid tyrosine into molecules that are then used by plants to create other molecules that plants need. This process of breakdown (catabolism) and the production of new molecules from the results (biosynthesis), is something that all living things do. HPPD inhibitors were first brought to market in 1980, although their mechanism of action was not understood until the late 1990s. At the time, they were primarily used in the Japanese rice production industry, but since the late 1990s have been used in Europe and North America for corn, soybeans, and cereals. Since the 2000s, they have become more important as weeds have become more resistant to glyphosate and other herbicides. Genetically modified crops which are resistant to HPPD inhibitors are under development. There is a pharmaceutical drug on the market, nitisinone, that was originally under development as an herbicide as a member of this class and is used to treat an orphan disease, type I tyrosinemia.
HPPD inhibitors can be classified into three fundamental chemical frameworks: pyrazolones, triketones, and diketonitriles. The triketone class is based on a chemical that certain plants make in self-defense called leptospermone; the class was developed by scientists at companies that eventually became part of Syngenta. Bayer CropScience has also been active in developing new HPPD inhibitors.
Mechanism of action The mechanism of action for HPPD inhibitors was misunderstood for the first twenty years that these products were sold, starting in 1980. They were originally thought to be inhibitors of protoporphyrinogen oxidase (protox).
4-Hydroxyphenylpyruvate dioxygenase (HPPD) is an enzyme found in both plants and animals, which catalyzes the catabolism of the amino acid tyrosine. Preventing the breakdown of tyrosine has three negative consequences: the excess of tyrosine stunts growth; the plant suffers oxidative damage due to lack of tocopherols (vitamin E); and chlorophyll is destroyed due to lack of carotenoids that protect it. Plants turn white without deformation due to a complete loss of chlorophyll, which has led compounds of this class to be classified as "bleaching herbicides", as are protox inhibitors.Wolfgang Kramer and Ulrich Schirmer, Modern Crop Protection Compounds (1)197-276(2012)
More specifically, inhibition of HPPD prevents the formation of a breakdown product, homogentisic acid, which in turn is a key precursor for the biosynthesis of both tocopherols and plastoquinone. Plastoquinone is, in turn, a critical co-factor in the formation of carotenoids, which protect chlorophyll in plants from being destroyed by sunlight.
This class of herbicides represents one of the last discoveries of a new herbicide mode of action in the wave of discovery that ended in late 1990s.
Resistance in weeds very little resistance was known: In 2010 Waterhemp (Amaranthus tuberculatus) in two different locations - Iowa and Illinois - developed resistance.
Products and economics
As of 2009, HPPD inhibitors had three fundamental chemical frameworks:George W. Ware and David M. Whitacre. An Introduction to Herbicides (2ndEdition) Extracted from The Pesticide Book, 6th ed*. (2004), Published by MeisterPro Information Resources, A division of Meister Media Worldwide, Willoughby, Ohio pyrazolones: pyrazolate (Sanbird, introduced by Sankyo, 1980); pyrazoxyfen (Paicer, introduced by Ishihara, 1985); benzofenap (Yukawide, introduced by Mitsubishi Chemical Corp and Rhône-Poulenc Agro, 1987, as of 2009 sold by Bayer CropScience as Taipan); pyrasulfotole (Huskie and Infinity, introduced by Bayer CropScience, 2007); and topramezone (Clio and Impact, introduced by BASF, 2006) triketones: sulcotrione (Mikado, introduced by Zeneca, 1990 and as of 2009 sold by Bayer CropScience)); mesotrione (Callisto and Lumax, introduced by Zeneca, 2002 and as of 2009 sold by Syngenta); benzobicyclon (ShowAce, introduced by SDS Biotech and Sandoz Crop Protection (now Syngenta), 2001); tembotrione (Laudis introduced by Bayer CropScience, 2007) diketonitriles: isoxaflutole (aka IFT) (Balance and Merlin, introduced by Rhône-Poulenc Agro, 1996 and as of 2009 sold by Bayer CropScience)
Agricultural use Pyrazolate, pyrazoxyfen and benzofenap were first commercialized in the Japanese rice market starting in 1980, but became less important when sulfonylurea herbicides were introduced. In 1990 sulcotrione was introduced for post- emergence weed control in corn. Isoxaflutole opened the market more broadly for HPPD inhibitors when it was introduced in 1996 for corn and sugarcane, and for use as a pre-emergence herbicide that could control broadleaf weeds as did sulcotrione, but also additional grass weeds. Benzobicyclon, was introduced in 2001 for control of broadleaf weeds and some sedges that are problems in rice, that had become resistant to sulfonylurea herbicides. Mesotrione was introduced in 2002 and like sulcotrione is a triketone, so it is effective on the same weeds and crops, but is more potent, making it more useful in mixes with other herbicides - an important factor for fully controlling weeds and preventing the development of resistance. It has become the biggest selling member of the HPPD class.
Topramezone was introduced in 2006 for corn and soy, and is the most potent HPPD inhibitor, but has serious carry-over issues especially for soybean in US, where the minimum time from application to planting is 18 months. Tembotrione was introduced in 2007 for corn, and works against key grass species and importantly, kills broadleaf weeds, including glyphosate-, ALS- and dicamba-resistant weeds. Used with safeners there are no crop-rotation restrictions. Pyrasulfotole was also introduced in 2007 for cereals in North America, and was the first new class of herbicide in cereals in many years, and an important advance against weeds that had become resistant to existing herbicides. It remains active in the soil during the growing season and when used with safeners, it does not damage crops and there are no crop-rotation restrictions.
Herbicide risks and toxicities
Tembotrione has low acute toxicity via the oral, dermal and inhalation routes of exposure (Toxicity category III or IV). It is a dermal sensitizer but not an eye or dermal irritantUS EPA Pesticide Fact Sheet: Tembotrione
Genetically modified crops To deal with rising resistance to existing herbicides, Bayer CropScience has been developing various genetically modified crops resistant to HPPD inhibitors: in one version, the crops are resistant to both HPPD inhibitors and glyphosate, and in collaboration with Syngenta, crops that are resistant to HPPD inhibitors and glufosinate.Gil Gullickson for Crops.com December 5, 2012 Something old, something new with herbicidesRhonda Brooks for Farm Journal February 12, 2014. "Seed Companies Pick Up the Pace on Seed Trait-Herbicide Systems"
The collaboration to develop the stacked HPPD inhibitor/glyphosate resistant products was first announced in 2007.Bayer CropScience press release. November 26, 2007 Bayer CropScience, Mertec and M.S. Technologies to Co-Develop New Soybean Trait Products
Medical use In Type I tyrosinemia, a different enzyme involved in the breakdown of tyrosine, fumarylacetoacetate hydrolase is mutated and does not work, leading to very harmful products building up in the body.National Organization for Rare Disorders. Physician's Guide to Tyrosinemia Type 1 Fumarylacetoacetate hydrolase acts on tyrosine after HPPD does, so scientists working on making these inhibitors hypothesized that inhibiting HPPD and controlling tyrosine in the diet could treat this disease. A series of small clinical trials were attempted with one of their compounds, nitisinone and were successful, leading to nitisinone being brought to market as an orphan drug.Sobi Orfadin (nitisinone)
Vector Control Use In addition to their use as herbicides and clinical treatments, certain HPPD inhibitors have shown potential for use in public health vector control, particularly against Anopheles mosquitoes. Nitisinone, a β-triketone originally approved for treating hereditary tyrosinemia type I in humans, has been demonstrated to kill mosquitoes through both systemic and contact exposure. When administered as an endectocide (i.e., via the bloodmeal), nitisinone disrupts tyrosine metabolism in blood-fed mosquitoes, leading to lethal toxic accumulation.
Nitisinone has also been shown to act as a contact insecticide, causing mortality after mosquitoes (Anopheles gambiae, Aedes aegypti and Culex quinquefasciatus) land on treated surfaces. In contrast, other HPPD inhibitors used in agriculture, such as mesotrione, sulcotrione, and tembotrione, do not appear to induce mosquito mortality through tarsal contact, limiting their potential for direct application in surface-based interventions.
History of the discovery of the triketone class of HPPD inhibitors The origin of the triketone family of HPPD inhibitors had its beginnings in the curiosity of a biologist about allelopathic weed control of weeds in the back yard of his house. This curiosity led to the discovery and development of the triketone class of herbicides. Investigation of the mode of action of this class of compounds led to the discovery that it could be used to treat patients with tyrosinaemia type 1, a treatment which has been said to "transform the natural history of tyrosinaemia".
All of the herbicidal and pharmaceutical triketone HPPD inhibitors including mesotrione (Callisto)(I),MeisterPro Crop Protection Handbook 2011, p.502 sulcotrione (Mikado)(II)MeisterPro Crop Protection Handbook 2011, p. 632 and nitisinone (Orfadin)(III)Christopher G. Knudsen, David L. Lee, William J. Michaely, Hsiao-ling Chin, Nhan H. Nguyen, Ronald J. Rusay, Thomas H. Cromartie, Reed Gray, Byron H. Lake, Torquil E. M. Frasier and David Cartwright, Discovery of the triketone class of HPPD inhibiting herbicides and their relationship to naturally occurring -triketones, Allelopathy in Ecological Agriculture and Forestry (2000), p. 101-111 had their common origin in the observation in 1977 by Reed Gray, a biologist at Stauffer Chemical's Western Research Center (WRC) in California, that few weeds emerged under bottlebrush plants (Callistemon citrinus) in the back yard of his house.
To investigate this effect, he took soil from underneath these plants and extracted and fractionated it. The resulting extracts were applied to soil flats containing watergrass (Echinochloa crus-galli) as an indicator species at the very high application rate of . There was a herbicidal effect from this test, so the extracts were developed on a preparative thin layer chromatographic sheet. The same Echinochloa crus-galli seeds were placed on this sheet and germinated. The active ingredient was identified by bleaching symptoms on the test species.
The area where the herbicidal activity was seen was extracted and he submitted the isolated active ingredient to Ken Cheng at the Western Research Center who, using proton NMR, IR and mass spectrometry identified the structure as being that of Leptospermone (IV) which was a known natural product that had been derived from the steam-volatile oils of some Australian plants, but which had never been cited as having any biological activity.