Inhibitors of lipoxygenase

Details Inhibitors of lipoxygenase Inhibitors of lipoxygenase

1998-04-01

2001-04-17

Witz, Jean C. (Department: 1651)

Drug, bio-affecting and body treating compositions

Antigen, epitope, or other immunospecific immunoeffector

Conjugate or complex

Reexamination Certificate

active

06217875

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to inhibitors of lipoxygenase.
BACKGROUND OF THE INVENTION
Technology of the Invention
This invention, in regard to inhibitors of lipoxygenase, is intended for application in medicines regulating or preventing allergic diseases, inflammatory responses or the like. It is intended for use in connection with non-medical supplies, such as cosmetics or food additives and so forth.
Earlier Development
Arachidonic acid, an essential fatty acid, exists inside the body as one compound of cell walls. Once arachidonic acid is stimulated, it is separated from phospholipid by the action of phospholipase. The separated arachidonic acid is metabolized by arachidonic acid metabolic enzymes e.g. lipoxygenase, then changed to substances such as prostaglandin (PG) which is associated with inflammatory responses or the like, *thromboxane (TX) which is associated with the formation of thrombus, and leukotriene (LT) and *lipoxyne, which induce allergic reactions. (See FIG.
1
).
Thus, arachidonic acid metabolic enzymes create substances which are the source of compounds that are associated with circulatory and allergic diseases, inflammation and so forth. Therefore, in order to regulate or prevent these diseases, it may be effective to inhibit the metabolism of arachidonic acid by enzyme action.
Some typical enzymes relating to the metabolism of arachidonic acid are 5-lipoxygenase, 12-lipoxygenase, and cyclooxynase (COX). 5-Lipoxygenase metabolizes arachidonic acid into 5-hydroxy-6,8,10,14-eicosatetraenoic acid (5-HETE), and induces the formation of leukotriene (LT) which is associated with allergic diseases, inflammatory responses and asthma. Also, 12-lipoxygenase is an enzyme having an arachidonic acid radical that metabolizes into 12-hydroxy-5,8,10,14-eicosatetraenoic acid (12-HETE). This compound is associated with arteriosclerosis, allergic diseases and metastasis of cancer.
Caffeic acid and quercetine or the like are well recognized as natural inhibitors of lipoxygenase. These substances, however, have not come into practical use as enzyme inhibitors. On the other hand, it is known that very few substances show significant inhibitory activity against 12-lipoxygenase. Other polyphenol group members are natural inhibitors of the activity of lipoxygenase. However, the inhibitory activity of these materials is not sufficient to produce satisfactory results in alleviating disease conditions. Further, it is difficult to cost-effectively purify enzyme inhibitors from natural substances.
Perilla (frutescens) seed is a year-round plant belonging to the perilla (crispa) family. It is indigenous to East Asia and is classified as an oil crop. Perilla (crispa) typically has a square-shaped stem, oval-shaped opposed leaves and small white flowers that bloom in the summer season. Its seeds are a little larger than those of perilla (crispa) and are harvested in the autumn.
Oil obtained from perilla (frutescens) seed is known as perilla oil, and is used as an ingredient in food or paint. Also, oil cake is used as fertilizer or feed. It has already been reported that perilla leaves contain physiologically active substances, however, there have been few studies of perilla (frutescens) seed.
As the result of investigations of rosemarinic acid and its methyl ester carried out by the inventors, from among the five substances that inhibit the enzyme activity of lipoxygenase, i.e.: luteolin, chrysoeriol, rosemarinic acid, rosemarinic acid methyl ester, and apigenin contained in perilla (frutescens) seed, it was found that Japanese Published Examined Patent Application No. 1-121217 has already described the inhibitory activity against 5-lipoxygenase associated with rosemarinic acid or its derivative extracted from fresh leaves of perilla (crispa) family.
Also, Japanese Published Examined Patent Application No. 8-510735 describes the inhibitory activity of apigenin on 5-lipoxygenase.
OBJECTS OF THE INVENTION
An imporantant object of this invention is to provide means to significantly inhibit the activities of 5-lipoxygenase and 12-lipoxygenase in relation to the metabolism of arachidonic acid.
Another object of this invention is to extract active inhibitors of lipoxygenase from natural substances that may be used to regulate and prevent allergic diseases, inflammatory responses, circulatory diseases and metastasis of cancer.
Other and additional objects of this invention will become apparent from a consideration of this entire specification, including the drawings hereof and the claims appended hereto.
BRIEF DESCRIPTION OF THE INVENTION
In accord with and fulfilling these objects, one aspect of this invention is the use of luteolin as an active compound to inhibit the enzyme action of lipoxygenase.
Another feature of this invention is the use of chrysoeriol as an active compound to inhibit the enzyme action of lipoxygenase.
Still another feature of this invention is the compounding of inhibitors of lipoxygenase from alcoholic extracts of perilla (frutescens) seed. These extracts comprise one or more compounds from among luteolin, chrysoeriol, rosemarinic acid, rosemarinic acid methyl ester and apigenin.
A further feature of this invention is that inhibitors of the enzyme action of lipoxygenase can be prepared from the alcoholic extract of perilla (frutescens) seed, including one or more compounds from among luteolin, chrysoeriol, rosemarinic acid, rosemarinic acid methyl ester, and apigenin. This alcoholic extract is suitably subjected to partition by ethyl acetate and water (two layers) and the fraction that partitions to the ethyl acetate layer is the desirable inhibitory fraction.
It may be preferable to use defatted perilla (frutescens) seed in place of the aforementioned untreated perilla (frutescens) seed. It is also possible to use perilla (crispa) seed in place of the aforementioned perilla (frutescens) seed.
The inventors have carried out various experiments on extracts of perilla (frutescens) seed, and have thereby discovered that an ethanol extract of perilla (frutescens) seed has a strong inhibitory effect against the enzyme action of 5-lipoxygenase and 12-lipoxygenase. As a result of a close study, the inventors have discovered that the luteolin, chrysoeriol, rosemarinic acid, rosemarinic acid methyl ester and/or apigenin in an alcoholic extract of perilla (frutescens) seed strongly inhibit lipoxygenase enzyme activity. It was found that luteolin especially has an outstanding inhibitory activity against lipoxygenase. The outstanding inhibitory activity of luteolin on lipoxygenase, together with the lesser inhibitory activity of chrysoeriol, has only come to light through the research of these investigations.
The inventors have also found, through various experiments on seeds of other varieties of perilla (crispa) belonging to the same family as perilla (frutescens), that alcoholic extracts of other seeds also contain substances that effectively inhibit the enzyme activity of lipoxygenase, i.e. luteolin, chrysoeriol. rosemarinic acid and rosemarinic acid methyl ester.
The structural formula of luteolin is as follows
It is known that luteolin exists as a glycoside generally in the bean family i.e. digitalis, etc. Also, it is known that luteolin has physiological activity as an anti-oxidant, a hyaluronidase inhibitor, and so forth.
According to this invention, when using luteolin as an active compound for its lipoxygenase inhibitory activity, it can be extracted or purified from the rind of citrus fruits as well as from perilla (frutescens) seed or perilla (crispa) seed and leaves. However, in industrial production, it may be preferable to use perilla (frutescens) seed or perilla (crispa) seed since the leaves contain only small amounts of luteolin.
The structural formula of chrysoeriol is as follows:
There are only a few reports of chrysoeriol having physiological activity as an anti-cancer agent or antibiotic. According to this invention, in order to use chrysoeriol as an active compound for its lipoxygenase inhibitory activity, it can be extracted or purifi

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