Use of antioxidants in companion animal disorders

Oxidation reactions occur in the mitochondria during normal cellular metabolism.

The transfer of electrons from one chemical species to another can form reactive oxygen species (ROS) in the cell. They have unpaired electrons that are attracted to surrounding lipids, proteins and nucleic acids in an attempt to stabilise their structures.

If left unchecked, ROS can damage DNA, organelles and lipid membranes¹. This damage is hypothesised to cause or promote many chronic conditions including arthritis, cancer, cardiovascular disease and ageing².

Antioxidant supplementation, on top of what is provided in the diet, has been suggested as a way to prevent or delay chronic disease progression in dogs and cats.

Antioxidant families

Enzymatic and non-enzymatic antioxidant systems exist in the cell to stop ROS-induced injury and to slow or prevent cellular damage (Figure 1).

Enzymatic systems include superoxide dismutase (SOD; copper-zinc or manganese), catalase and glutathione peroxidase. Non-enzymatic antioxidants include vitamin C, vitamin E, carotenoids (for example, b-carotene and lycopene), thiol antioxidants (for example, glutathione, lipoic acid and S-adenosylmethionine; SAMe) and flavonoids (polyphenolic compounds).

Both forms of antioxidant work to prevent free radical damage to the cellular structure, but in different ways. Enzymatic antioxidants convert the ROS to less reactive compounds, such as water and oxygen, while non-enzymatic antioxidants donate an electron to “quench” the ROS.

The balance between ROS formation and antioxidant capacity of the cell depends on the antioxidant systems’ demand and the dietary intake of all antioxidant compounds.

Antioxidants in health and disease

Healthy dogs and cats eating complete and balanced diets do not need antioxidant supplementation, though at certain life stages (geriatrics) and with certain conditions (for example, liver disease) the minimum requirements may not meet whole body antioxidant demand.

Total body antioxidant status relies on indirect indicators of oxidative stress (for example, isoprostane and malondialdehyde in urine) and antioxidant levels (for example, a-tocopherol and glutathione peroxidase in lymphocytes).

These diagnostic tests are not routinely available outside academic or industry settings; general practice and non-academic referral veterinary surgeons are often unsure of when to recommend supplementation.

Geriatrics

Supplementation with enzymatic and non-enzymatic antioxidants may benefit geriatric cats and dogs (Figure 2). When supplemented into the diets of otherwise healthy adults, vitamin E for cats³ and b-carotene for dogs⁴ improved immune function.

Studies in older dogs receiving a mixed supplementation also showed better retention of learned behaviours compared to age-matched controls⁵, but there is debate about the “correct” blend of antioxidants to see these effects.

Many formulations of dietary antioxidants are available and are generally considered safe, though safety and efficacy data for most single agent and combination antioxidant blends are lacking.

Supplementation should be used with caution in cats as certain compounds that appear safe for dogs and humans may be toxic or potentiate toxic reactions (for example, lipoic acid⁶).

Liver disease

The liver is integral in the detoxification of protein metabolites, production of serum albumin and clotting factors, storage of vitamins and minerals, and metabolism of ingested phytochemicals and drugs.

Chronic hepatitis increases ROS production in the liver⁷ and can perpetuate oxidative damage. Certain compounds are increasingly being used as hepatoprotectants with antioxidant function (Figure 3):

• Silymarin (milk thistle seeds extract) increases hepatic glutathione concentrations and can protect against Amanita-induced liver toxicity in dogs⁸. It may also promote hepatocyte regeneration in other forms of liver disease and drug-induced hepatic dysfunction, but clinical studies have not been performed to date. It is generally considered safe for dogs and cats, but there are sporadic cases in humans of adverse gastrointestinal signs (abdominal pain, vomiting and diarrhoea) with chronic supplementation.
• SAMe functions as a methyl donor for many endogenous compounds (such as taurine, glutathione, catecholamines and neurotransmitters). Its role in liver disease may be related to either improved antioxidant status⁹ or support of hepatocyte regeneration and detoxification of drug compounds^10,11. The presence of food in the stomach can decrease SAMe absorption, so give this supplement on an empty stomach one to two hours before a meal.
• Vitamin E is a membrane-bound intracellular antioxidant, which helps protect the membrane phospholipids from peroxide damage. Fat-soluble vitamin E needs bile salts for absorption from the intestinal tract, but in animals with cholestatic disease absorption is decreased. In these animals, a water-soluble form of the supplement may be required.

Heart disease

Reactive oxygen species cause cellular damage, have negative inotropic effects and perpetuate inflammatory responses in animals with heart disease.

Dogs with congestive heart failure due to dilated cardiomyopathy or chronic valvular disease have more biomarkers of oxidative stress and damage and low circulating levels of glutathione and vitamin E^12,13.

There are no published interventional studies about antioxidant supplementation helping this group of patients.

Cancer

Excess ROS in the cell (above its antioxidant capacity) can damage membrane lipids, cause single or double-
stranded DNA breaks, modify protein structures and cross-link DNA. It can lead to arrest or induction of transcription, replication errors and genomic instability.

Increased oxidative stress markers and low plasma levels of measured antioxidants have been found in dogs newly diagnosed with lymphoma¹⁴ and dogs with mammary carcinomas¹⁵.

Literature about antioxidant supplementation and cancer incidence in humans shows mixed results. Certain antioxidants lower incidences, but others may increase the risk of specific cancer and have been linked to higher mortality:

• Dietary intake of both enzymatic and non-enzymatic antioxidants may prevent tumorigenesis¹⁶, but the benefits of increasing antioxidant intake in dogs and cats are largely theoretical. Many cancer treatments rely on ROS formation to induce cancer cell death, so avoid antioxidant supplements in patients undergoing chemotherapy and radiation therapy.
• Moderate vitamin E intake (200IU/day) in humans may lower the incidence of colorectal cancers, but higher intake (>400IU/day) failed to protect and was associated with a higher risk of death¹⁷. Vitamin E is generally considered safe for dogs and cats and used routinely with liver disease, but high dose supplementation for cancer prevention has not been evaluated.
• Less intake of vitamin C in humans has been linked to gastric and colorectal precancerous changes¹⁸, but prospective supplementation studies have shown varied results by cancer type^19-22. Vitamin C supplementation may protect against lung and colorectal tumours¹⁹, but showed no effect on the development of alimentary tumours compared to placebo^20-22. Cats and dogs synthesise vitamin C endogenously, so it is not a required dietary nutrient. The effect of supplemental vitamin C intake on canine and feline cancers has not been studied.
• Increased flavonoid intake may reduce stomach, pancreatic and lung cancers in people²¹, but higher intake of certain flavonoids has been linked to hepatic failure, contact dermatitis and haemolytic anaemia in people²³. Safety and efficacy of flavonoid compounds in dogs and cats is lacking, but a safety study of green tea extract (a type of flavonoid supplement) in healthy beagles showed a high morbidity and mortality rate, prompting early termination of the study²⁴. Flavonoids should be used cautiously in veterinary medicine.

l Selenium has been evaluated in dogs as an interventional therapy. Higher intake in older male dogs without a history of prostatic disease showed a drop in DNA damage to prostatic tissue, compared to non-supplemented controls, and higher apoptosis of prostatic cells²⁵.

Summary

Companion dogs and cats are increasingly viewed as integral members of the family and their nutritional needs have changed from meeting minimal requirements to optimising intakes for long-term health and well-being.

Good evidence exists for incorporating antioxidants into everyday practice for older animals and those with liver or heart disease. Antioxidants may also help prevent cancer, but once cancer has been diagnosed avoid both enzymatic and non-enzymatic supplements (including flavonoids) to prevent inadvertently protecting cancer cells during radiation or chemotherapy.

Antioxidants may also benefit canine athletes (to balance the increased oxidative stress during periods of strenuous activity) and other chronic inflammatory conditions (such as diabetes mellitus, inflammatory bowel disease or arthritis), though interventional studies are largely lacking.

Antioxidant supplementation may promote health and well-being and help manage certain diseases in companion dogs and cats. Their use should be considered by veterinary surgeons.