https://digitalcommons.andrews.edu/cgi/viewcontent.cgi?article=3516&context=pubs

Health-promoting properties of common herbs

A Cook's tour is presented of the organosulfur chemistry of the genus Allium, as represented, inter alia, by garlic (Allium sativum L.) and onion (Allium cepa L.). We report on the biosynthesis of the S-alk(en)yl-L-cysteine S-oxides (aroma and flavor precursors) in intact plants and on how upon cutting or crushing the plants these precursors are cleaved by allinase enzymes, giving sulfenic acids—highly reactive organosulfur intermediates. In garlic, 2-propenesulfenic acid gives allicin, a thiosulfinate with antibiotic properties, while in onion 1-propenesulfenic acid rearranges to the sulfine (Z)-propanethial S-oxide, the lachrymatory factor (LF) of onion. Highlights of onion chemistry include the assignment of stereochemistry to the LF and determination of the mechanism of its dimerization; the isolation, characterization, and synthesis of thiosulfinates which most closely duplicate the taste and aroma of the freshly cut bulb, and additional unusual compounds such as zwiebelanes (dithiabicyclo[2.1.1]hexanes), a bis-sulfine (a 1,4-butanedithial S,S′-dioxide), antithrombotic and antiasthmatic cepaenes (α-sulfinyl disulfides), and vic-disulfoxides. Especially noteworthy in the chemistry of garlic are the discovery of ajoene, a potent antithrombotic agent from garlic, and the elucidation of the unique sequence of reactions that occur when diallyl disulfide, which is present in steam-distilled garlic oil, is heated. Reaction mechanisms under discussion include [3, 3]- and [2, 3]-sigma-tropic rearrangements involving sulfur (e.g. sulfoxide-accelerated thio- and dithio-Claisen rearrangements) and cycloadditions involving thiocarbonyl systems. In view of the culinary importance of alliaceous plants as well as the unique history of their use in folk medicine, this survey concludes with a discussion of the physiological activity of the components of these plants: cancer prevention, antimicrobial activity, insect and animal attractive/repulsive activity, olfactory–gustatory–lachrymatory properties, effect on lipid metabolism, platelet aggregation inhibitory activity and properties associated with ajoene. And naturally, comments about onion and garlic induced bad breath and heartburn may not be overlooked.

The Organosulfur Chemistry of the Genus Allium – Implications for the Organic Chemistry of Sulfur

Chemoprevention of cancer.

Herbs are often administered in combination with therapeutic drugs, raising the potential of herb-drug interactions. An extensive review of the literature identified reported herb-drug interactions with clinical significance, many of which are from case reports and limited clinical observations. Cases have been published reporting enhanced anticoagulation and bleeding when patients on long-term warfarin therapy also took Salvia miltiorrhiza (danshen). Allium sativum (garlic) decreased the area under the plasma concentration-time curve (AUC) and maximum plasma concentration of saquinavir, but not ritonavir and paracetamol (acetaminophen), in volunteers. A. sativum increased the clotting time and international normalised ratio of warfarin and caused hypoglycaemia when taken with chlorpropamide. Ginkgo biloba (ginkgo) caused bleeding when combined with warfarin or aspirin (acetylsalicylic acid), raised blood pressure when combined with a thiazide diuretic and even caused coma when combined with trazodone in patients. Panax ginseng (ginseng) reduced the blood concentrations of alcohol (ethanol) and warfarin, and induced mania when used concomitantly with phenelzine, but ginseng increased the efficacy of influenza vaccination. Scutellaria baicalensis (huangqin) ameliorated irinotecan-induced gastrointestinal toxicity in cancer patients. Piper methysticum (kava) increased the ‘off’ periods in patients with parkinsonism taking levodopa and induced a semicomatose state when given concomitantly with alprazolam. Kava enhanced the hypnotic effect of alcohol in mice, but this was not observed in humans. Silybum marianum (milk thistle) decreased the trough concentrations of indinavir in humans. Piperine from black (Piper nigrum Linn) and long (P. longum Linn) peppers increased the AUC of phenytoin, propranolol and theophylline in healthy volunteers and plasma concentrations of rifamipicin (rifampin) in patients with pulmonary tuberculosis. Eleutheroccus senticosus (Siberian ginseng) increased the serum concentration of digoxin, but did not alter the pharmacokinetics of dextromethorphan and alprazolam in humans. Hypericum perforatum (hypericum; St John’s wort) decreased the blood concentrations of ciclosporin (cyclosporin), midazolam, tacrolimus, amitriptyline, digoxin, indinavir, warfarin, phenprocoumon and theophylline, but did not alter the pharmacokinetics of carbamazepine, pravastatin, mycophenolate mofetil and dextromethorphan. Cases have been reported where decreased ciclosporin concentrations led to organ rejection. Hypericum also caused breakthrough bleeding and unplanned pregnancies when used concomitantly with oral contraceptives. It also caused serotonin syndrome when used in combination with selective serotonin reuptake inhibitors (e.g. sertraline and paroxetine). In conclusion, interactions between herbal medicines and prescribed drugs can occur and may lead to serious clinical consequences. There are other theoretical interactions indicated by preclinical data. Both pharmacokinetic and/or pharmacodynamic mechanisms have been considered to play a role in these interactions, although the underlying mechanisms for the altered drug effects and/or concentrations by concomitant herbal medicines are yet to be determined. The clinical importance of herb-drug interactions depends on many factors associated with the particular herb, drug and patient. Herbs should be appropriately labeled to alert consumers to potential interactions when concomitantly used with drugs, and to recommend a consultation with their general practitioners and other medical carers.

Herb-drug interactions: a literature review.

The medicinal use of garlic dates back thousands of years, but there was little scientific support of its therapeutic and pharmacologic properties until recently. In the past decade, the cancer-protective effects of garlic have been well established by epidemiologic studies and animal experiments. However, the cardiovascular-protective properties of garlic are less well understood. In particular, despite the reported hypocholesterolemic effect of garlic, the mechanism of the effect is unclear. In a recent randomized, double-blind, placebo-controlled intervention study, we showed that aged garlic extract (AGE) supplementation was effective in lowering plasma concentration of total cholesterol by 7% and LDL cholesterol by 10% in hypercholesterolemic men compared with subjects consuming a placebo. Supplementation of AGE in animal diets similarly reduced plasma concentrations of total cholesterol and triacylglycerol by 15 and 30%, respectively. In subsequent experiments using cultured rat hepatocytes, we found 44--87% inhibition of cholesterol synthesis by the water-extractable fraction (WEF), methanol-extractable fraction (MEF) and petroleum ether-extractable fraction (PEF) of fresh garlic, and Kyolic (liquid form of AGE). These observations suggested that hydrophilic and hydrophobic compounds of garlic are inhibitory to cholesterol synthesis. Because S-allylcysteine (SAC) alone was less potent than Kyolic, which contains SAC and other sulfur compounds, a maximal inhibition appears to require a concerted action of multiple compounds of garlic. In a series of experiments, we further characterized the inhibitory potency of individual water-soluble and lipid-soluble compounds of garlic. Among water-soluble compounds, SAC, S-ethylcysteine (SEC), and S-propylcysteine (SPC) inhibited cholesterol synthesis by 40--60% compared with 20--35% by gamma-glutamyl-S-allylcysteine (GSAC), gamma-glutamyl-S-methylcysteine (GSMC) and gamma-glutamyl-S-propylcysteine (GSPC). Lipid-soluble sulfur compounds (i.e., diallyl sulfide, diallyl disulfide, diallyl trisulfide, dipropyl sulfide and dipropyl trisulfide) at low concentrations (0.05--0.5 mol/L) slightly (10--15%) inhibited cholesterol synthesis but became highly cytotoxic at high concentrations (1.0--4.0 mol/L). All water-soluble compounds, except S-allylmercaptocysteine, were not cytotoxic, judging from the release of cellular lactate dehydrogenase into the culture medium. Taken together, the results of our studies indicate that the cholesterol-lowering effects of garlic extract, such as AGE, stem in part from inhibition of hepatic cholesterol synthesis by water-soluble sulfur compounds, especially SAC.

Daniel W. Nixon

Papers

Garlic: a review of its relationship to malignant disease.

Chemoprevention and modern cancer prevention.

Prevention and detection.

Nutrition and cancer: American Cancer Society guidelines, programs, and initiatives.

Preventive medicine in the year 2000