Indian Journal of Experimental Biology Vol. 37, February 1999, pp. 109-116

Review Article

Role of nutrition in toxic injury

Shayam Bala Lall, Bhoopendra Singh, Kavita Gulati & S 0 Seth

Department of Pharmacology, All India Institute of Medical Sciences, New Delhi-II 0 29

The importance of nutrition in protecting the living organism against the potent ially lethal effects of reactive oxygen species and tox ic environmental chemicals has recently been realized. This new perspective has prompted re-evaluat ion of the food constituents of human diet from the point of view of their nutritional adequacy, deficiency and toxicity. The biological antioxidant defense system is an integrated array of enzymes, antioxidants and free radical scavengers. These include glutathione reductase, glutathione-s-transferase, glutathione peroxidase, phospholipid hydroperoxide glutathione peroxidase, superoxide dismutase (SOD) and catalase, together with the antioxidant vi tamins C, E and A. The individual components of this system get utilized in various physiological process and for chemoprotection and therefore require repleni shment from the diet. Other components of the diet li ke carbohydrates, prote ins and lipids are important for maintaining the levels of various enzymes required in body's defense system provid ing protection against carcinogens. However, the emerging newer concepts focus on the role of trace elements and other dietary components in antiox idant defense and detox ification mechanisms. Trace elements like Iron, zi nc magnesium. seleni um. copper, and manganese are some of the elements invo lved in antiox idant defense mechanisms. Inadequate intake of these nutrients has been associated with ischemic heart disease, arthritis, stroke and cancer. where pathogeni c role of free radicals is suggested. Further the importance of diet in the prevention of chemical induced toxicity can not be undetermined. Recent reports on the ro le ofbiofl avunoids as an ti ox idents and their potential use to reduce the ri sks of coronary heart disease and cancer in human beings have opened a new arena for fu ture research. Induction of the cytochrome P4S0 isoenzymes by food pyrolysis, mutagens. alcohol and fasting, on the other hand is reported to contribute to chemical toxicity and carcinogenec ity. Certain chemicals moieties in the food are mutagen ic and carcinogenic.

Role of nutritioll in toxic illjury

It is generally considered that good nutrition is required for growth , muscular work, maintenance of body temperature, ti ssue repair, and defense aga inst infection. Recent reports indicate importance of nutrition in protecti ng the li ving organism aga inst the potentiall y lethal effects of reacti ve oxygen spec ies and tox ic environ menta l chemicals 1.2 The diet and nutritional status of the individual also influences biotransformation of drugs in the bodi-4

The biologica l defense system exists to protect an organism from damaging effects of (i) tox ic chemicals in the enviro nment and (ii ) reacti ve oxygen spec ies (RqS) generated. The detox ication and antiox idant biologica l systems have an essential common component, that is reduced glutath ione (GS H) (Fig. I). It is now recogni zed that many aspects of chemica l tox icity are mediated by both the systems. The bio logical antiox idant defense system is an integrated array of enzymes, antioxidants and free radica l scavengers. These include GS H, glutathione reductase, glutathione-s-transferase, glutathione perox idase , phospho­lipid hydraperox ide gl utathione perox idase, superox ide di smutase (SOD) and catalase , asco rbic ac id (v itamin C) , tocophero ls (v itamin. E), and carotenoids5

.6 Adequate

NA DPH is req uired fo r maintaining the intracellular reduced glutath ione leve ls. The effi ciency of the individual components large ly depend on the the d iet that rep leni shes their stores. Protein intake in addition to its ro le as normal nutrient is required for the synthes is of su lfur containing detox ifying enzymes (glutathion) and glyc ine. Glutathione in turn is also essential for conjugation reactions in li ver.

Phospholipids and lipotropes are needed for the synthes is of bio logica l membranes including those of hepatic endoplasmic reti culum, where detox ification of ' most xenobiotics takes place.

Carbohydrates prov ide energy and glucuronoids are required for conjugation. Antiox idant vitamins are scavenge oxygen free radica ls. Iron is needed for heme prote in synthes is and in the synthes is of cytochrome P450 enzymes.

Thus altered nutritional status li ke protein energy malnutrition (PEM), anae mia, defic iency of vi tami ns, minerals and trace elements may lead to significant pathophys iologica l changes in the body which in turn affect the respoll ses to drugs and chemicals"s The ox idati ve/antiox idati ve pro fil e was observed to be more severely affected with coex istence of prote in energy malnutrition in Ri fa mpicine (RMP) treated rats9

Further, di et and nutrir ion are we ll known to have profound effect on the pharmaco logica l and tox ico logical responses of laboratory animals to drugs and environmenta l chemicals. Therefore, these major vari ab les could be conside rd when animal pharmacokinetic or pharmacodynamic studies are undertaken or long-term animal tox icity and carcinogencity study protoco ls are des igned.

Ellergy requirement for biological defence systems

Cellular energy is required for the generation ofN ADPH from NA DP, for regeneration of reduced glutathion fro m ox idized gl utathione and for acti vation of cytochrome P450. Many hepatotoxic chemicals exert their tox ic effects

110 INDIAN J EXP BIOL, FEBRUARY 1999

by interfering with cellular energy production. Fructose 1,6-dipbo!'phate, a readily available source of ATP, increases liver . A TP levels, polyamine synthesis and hepatic regeneration and thus decrease liver inj ury 10. Protein­energy nutrition also affects the activity of cytochrome P450. A deficiency in energies enhances the activity of P45011EI and probably P450IV, the inducer of m~Jta­

genesis II . Oral administration of glucose for 48 hr to rats inhibited the in vitro microsomal metabolism of benzo­pyrene, and DNA adduct formation12 . Energy deficiency especially low intake of protein is reported to cause a 20 to 40% decrease in phenazone and theophyline clearance respectively I3 . in contrast, in rodents normal diet caused higher oxygen consumption, decreased insulin binding and modified gene expression compared with animals on restricted diet l4

. Energy restricted rats were completely refractive to 7, 12- dimethylbenzene (a) anthracene induced mammary tumors l5 while those on unrestricted diet showed progressive age-related degradation of the antioxidant enzymes l4

.

Fasting and toxic injury

In 1979, Pessayre drew attention to the marked difference between the hepatotoxicity due to liver toxins, bromobenzene and acetaminophen,in fed and fasted rats 16.

It was shown that rats fasted for 24 hr manifested hepatotoxicity at an oral dose of 125 mg/kg of bromobenzene whereas fed rats showed no toxicity even at six times this dose level which is suggested to be due to depleted levels of liver glutathione observed in 24 hr fasted rats. Similarly, overnight fasting is reported to evoke major changes, both qualitative and quantitative, in res­ponsiveness of opioids3

,4 . In general, fasting induces aipid peroxidation, reduced levels of microsomal enzymes and antioxidants, resulting in decreased dptoxication and weakening of body's defense mechanisms I ', .

Carbohydrate and Toxic Injury

The effect of dietary carbohydrate on xenobiotlc metabolism has received relatively little attention. Generally, a high carbohydrate (low protein and/or lipid) diet is reported to decrease the rate of detoxification. Kato l8

and Campbell and Hayes l9 have shown that 'high carbohydrate diet increases barbiturate sleeping time in mice and benzylpenicillin mortality in rats l9

. When a rat diet contained sucrose rather than equal parts of sucrose, glucose and com starch, the lipogenic effect of phenobarbital and aflatoxin-induced hepatic preneopi.astic lesions were enhanced20

. A number of studies have shown that both glucose and fructose modulate cytochrome !P450 activity and carcinogen activation in rats2 1

.22

. Potentiation of N-nitrosomorpholine induced carcinogenesis in ra1:S by dietary fructose has also been reported23

.

Protein and toxic injury

Dietary protein is essential for the biosynthesis of glutathione, the intracellular redox buffer, which provides

the ultimate protection against the toxic effects of ROS, It also helps in detoxicating environmental chemicals and their metabolites (epoxides) by conjugation (Fig. 2) . The amino acids glycine, glutamate, cysteine and taurine are involved in the conjugation of drugs, and also their metabolites (Phase II reactions) and environmental chemicals. The sulfur containing amino acids (cysteine, methionine etc.) are oxidized to yield sulphates which help in conjugation and detoxication of phenol's and other chemicals. Hepatic mixed-function oxidase activities increase with increase in dietary proteins24

. In rodents, fed with high protein diet, acute oral toxicity of a number of pesticides (lindane, malathione, DDT, carbaryl and captan) have been shown to be reduced25

. Similarly, high protein diet decreased the 7,12-dimethylbenz (a) anthracene­induced incidence of breast cancer26 and N-methyl-N'-nitro­nitrosoguanidine induced gastric cancer27. Oxidative drug metabolism (phase I reactions) of antipyrine, theophylline, propranolol and other drugs in humans is increased with protein rich diet. Methionine deficiency is reported to increase the hepatotoxiCity of paracetamol in rats28

Dietary proteins can influence the rate of absorption of orally administered xenobiotics. Concomitant intake of proteins and mi idly acidic drugs (aspirin and barbiturates) or alcohol results in decreased of these drugs absorption because of buffering action of proteins. Conversely, a high protein meal results in enhanced absorption of basic drugs like theophylline29

. Protein-deficient diets can either depress or enhance activation of procarcinogens to reactive metabolites. The binding of aflatoxin metabolites to DNA is depressed by protein-deficient diet which is correlated with decreased hepatic tumor response30

. In contrast, a high­protein diet leads to less binding of 7, l2-dimethyl­benzanthracene metabolites to DNA and decreased mammary tumor response3 1

. In a classic study, Kato and his colleagues32 demonstrated that protein-deficient rats exhibited decreased metabolism and increased mortality with strychnine, pentobarbital, and zoxazolamine. In contrast, when the metabolite is toxic, a protein-deficient diet protected against toxicity. For example the toxicity of octamethylpyrophosphoramide and heptachlore is decreased as these are not activated to epoxides by the ox idases32,33.

Lipids and toxic injury

Lipids are source of energy for normal functioning of the body. Pho~pholipids and polyunsaturated fatty acids (PUFA) are essential for the synthesis of biological membranes, prostaglandins and other prostanoids. Cholesterol is required for the synthesis of steroid hO'rmones and bill': acids. Nevertheless, high fat diet promotes the incidence of cancer and potentiates the tumorogencity of aflatoxins, N-nitrosodiethylamine, 1,2-dimethylhydrazine, and 2-acetylaminofluorene34

. Low dietary intake of lipotropes, choline, methionine, glycine, folate, vitamin B 12, pyridoxal, polyunsaturated fatty acids

LALL et at.: NUTRITION & TOXIC INJURY III

and phosphates, which are essential for microsomal metabolism detoxication of xenobiotic chemicals is associated with carcinogenesis. Further, choline deficient diet resulted in lipid peroxidation and hepatotoxicity in rats within days and induced hepatocellular carcinoma in >50% of the animals within two years even in the absence of any carc inogen or toxic chemical35 Com oil and fi sh oil (5%) in the diet increased liver epoxide-hydrolase, glutathione-s­transferase, UDP-glucuronyl transferases as compared to an isocaloric fat free diet in animals36. The com oil and lard as a fat sources, significantly increase aortic oxidative stress and excessive dietary intake may significantly contribute to the injury of the vessel wa1l37

Dietary fat is shown to affect the mi xed function oxidase enzyme system, both quantitatively and qualitatively. PUFA are not only essential fo r membrance biosynthesis but also important in biotransformation of xenobiot ics. However, paradoxically increased in take of PUFA enhances lipid peroxidation, activation of carc inogens like benzo(a)pyrene and susceptibil ity of membranes to peroxidative stress's. Diets containing 17.5% of highly unsaturated sunflower seed oil (PUFA) resulted in depressed hepatic microsomal oxidative activi ty. and increased phenobarbi tone sleeping times, compared to the use of less saturated tallow di et39

Cardiotoxic effect of adriamyc ine was enhanced when rats were fed 53%, chaw with 39.7% butter and 5% cholesterol, an extremely nutritional modulation, that resu lted in numerous pathological changes prior to administration of the adriamycine40

Vitamins and toxic injury

Vitamins (rhodopsin, ascorbic acid , tocopherol, riboflavin and folate) function as antioxidants and prevent xenobiotic induced lipid perox idation and ge!leration of oxygen free rad icals (F ig. 2) . Vitamin C reduces chemical toxicity by decreas ing the covlent binding of reactive intermediate, reducing quinones, elim inating free radical metabolites, inhibiting the formation of toxic nitrosamines and facil itating xenobiotic elimination by conjugation to glucuronides41. Kanazawa el al4 2 reported that ascorbic acid deficiency in guinea pigs led to decrease in CY PIA I and CYPII E isoforms of cytochrome P450, responsible for activation of aflatoxin, a cooked-food heterocyclic amine carcinogen. Recently Vitamin C and E have been shown to reduce the extent and severity of gastric ulcer resulting fro,m immobilization- stress and al so to enhance the immunity in rats43,

Vitamin E is shown to be an important antiox idant, scavenging free radicals and reducing reactivity of singlet oxygen thus protecting the microsomal membranesagainst lipid peroxidation and ensuing loss of cytochrome P45044

It has been used clinica lly in a variety of oxidation related diseases45 , Vitamin E ameliorates both the cardiac damage and carcinogenecity of the quinones, adriamycin and daunomycin, which are mutagenic, carcinogenic, cause cardiac damage and are toxic because of free radical generation46, Protective effects of tocophero l against radiation-induced DN A damage and mutation and

dimethylhydrazine-induced carcinogenesis have also been observed47, Paro la e/ al,48 demonstrated th~t Vitamin E supplementation provides protection against carbon tetrachloride induced chronic liver damage and cirrhosis in rats , Similarly, dietary supplementation inhibited dimethyl­benz (a) anthracene-induced lipid peroxidation and the associated development of mammary tumors in rats49

,

p-Carotene is another antioxidant in the diet that is important in protecting lipid membranes against oxidation , Carotenoids are free radical traps and quenchers of singlet oxygen. p-carotene is present in carrots, turnips and sp inach , Carotenoids have been shown to be anti­carcinogens in experimental animals and in humans50.53 , Thei r protective effects against smoking induced free radical injury has been reported54.55, Vitamin A and retionoids have a protective effect against chemical carcinogens , Their defic iency increased the binding of benzo (a) pyrene metabolites to DNA, thereby increasing the in ::idence of respiratory tumors in hamsters56, Further, carotenoids have been shown to inhibit the carcinogenicity of benzo (a) pyrene , mutagenicity of aflatoxin and the aminoimido-aza-arenes57.5R

. In contrast, retinoid deficiency did not significan tly affect li ver cytochrome P450-dependent mixed fu nction ox idase or glutathione-s­transferase activities59

Riboflavin is an essential component of the NADPH­cytochrome P450 reductase system, Diet deficient in riboflavin is shown to result in abnormal P450 reductase, electron uncoupling and reactive oxygen species (ROS) generation. Riboflavin also potentiates ni tro- and azo­reductase activity and enhances the efficacy of su lfasalazine, an anti-inflammatory drug, in the treatment of ulcerative colitus60, Dietary folates are also required for drug metabolism and chemical detoxication . Labadarios61

reported that diet deficient in fo lates led to enzyme induction, progress ive decrease of drug metaboli sm, and teratogenic effects in the offsprings of epi leptics tak ing phenobarbitone and diphenylhydantoin therapy.

Fruits and vegetab les are very important part of the nutrition in providing protection aga inst ROS and the adverse effects of drugs and toxic chemicals62 Flavonoids are polyphenolic antioxidants that occur in a variety of foods from vegetable origin, such as apples, onions, tea, and red wineo3

,64, These are considered to be nonnutriti ve compounds65 however, quercetin a flavonoid is rep0l1ed to inhibit carcinogenesis in rats66

•68 and to inhibited colonic

~ll proliferat ion in vitro69, In addition, some flavonoids,

scavenge superoxide anions70, singlet oxygen71 and lip id peroxy radicals72 and reduce oxidabil ity73 and cytotoxic effects of low density lipoproteins (LDLs)32 Intake of antioxidant flavonoids might therefore conceivably reduce coronary heart disease (CHD) and cancer ri sk in human be ings. Flavonoids are also reported to protect against hepatotoxicity74,

Isothiocyanates and alkyl sulfides found in allium species and in other vegetables are dietary anticarcinogens which act by increasing glutathione-s-transferase act iv ity75

1. 12 INDIAN J EXP BIOL, FEBRUARY 1999

76 d h . Recently, Wang et al. demonstrate epaloprotectlve effect of garlic on acetaminophen induced toxicity in mice. Sedanolide and other phthalides presen t in celery act as anticarcinogens and are shown to induce glutathione-s­transferase acti vi ty by 5- folds in liver and bowel mucosa77

Trace elements in toxic injury Recent reports on the role of trace elements in the

cellular metabol ism have necessitated moni toring and quantification of the essential and toxic elements in human diet. The fifteen trace elements present in the body in micro concentrat ions (arsenic, chromium, cobalt, copper, fluorine , iodine, iron , magnes ium, molybdenum, nicke l, selenium , sil icon, tin, vanadium and zinc) are considered essential. According the new definition of essentiali ty of trace elements (TEs) di scussed by Xiu YM 78, only ten TEs (Fe, Zn, F, Cu, I, Se, Mn, Mo, Cr, Co) are considered to be essent ia l to humans. Out of these mai nly Se, I, Fe, and Zn are more closely related to publ ic hea lth . Also emphases are laid on balancing all nutrients when new knowledge of essentia l TEs is applied in public hea lthn. As defic iency of individual element results in impa irment of a function which is prevented or corrected by supplementation with physio logical levels of that particular element. The deficiencies of essential trace elements during early development can resul t in structural abno rmal it ies and l or embryonic death . In contrast a small excesses of essent ial meta ls can also have negative effects on the deve loping embry079

Iron and zinc are important elements required for biosynthes is of heme, cytochrome P450, and mixed­funct ion oxidase system34

.XO However, excess of these may

enhance the product ion of ROS resulting in lip id peroxidatioll destruct ion of cytochrome P450, and loss of

. .' . . . RO R I , 82 mixed fU!1c tlOn OXidase activi ty . . Ne lson I!t (/1. reported that increased dietary iron can promote 1,2-dimethyl­hydrazine ind uced colorectal cancer in ra ts which cou ld be reve rsed by phytic acid present m the dietary fiber.

Zinc has an tianaphylactic and an tisecretary propert ies that may contribute to its capacity to prevent in testinal dysfunction du ring malnu triti on83

.

Selenium is also essent ial for maintenance of an optimal . 84 Imm une response .

Manganese and boron also play an important role in . . I h ~ antiox idant defe nse system III anInla s an umar.s .

Manganese is a component of the manganese superoxide dismutase, specific cofactor for several enzymes and nonspeci fic act ivator of many other enzyrm:s, which are involved in the protect ion of the cell from n'ee radic:lI c1amage8(,.

Chromium is an essential nutrient requi red for sugar and fdt metabo li sm. 'onna l dietary intake of Cr in humans is us uall y subopt imal. Insufficient dietary intake leads to signs and symptoms of diabetes and cardiovascular di sease.

i1pplementa tion Cr leads to improved bl ood glucose, insulin , li pid vari ables and lean body mass. Trivalent chromium has a very large saft' ty range and there have been

no documented signs of Cr toxicity in any of the nut ritional studies at levels up to I mg/da/7

Experimental evidences indicate that adverse effects of heavy metals (cadmium, lead, arsenic and mercury ) are antagonized by some essential elements (Zn, Cu, Se etr .) and on the other hand the heavy metal tox ici ty is shown to . . d fi . fit 88 8 Increase In e lClencyo trace e emen s . .

Aluminium is commonly used in food processing, storage, pharmaceuticals and as phosphate binder in diet. It can be ingested in trace amounts. Prol ongcd exposurc and resu ltant body accumu lations can lead to fregnent bone fracturer, osteodystrophy, secondary hype rparathyroidism and altered myocardial calcium transport90

Ex perimental and epidem iological stud ies suggest that dietary copper is essentia l for nonna l cardiovascular funct ion. Inadequate intake of specific trace elements have been suggested to contri bute and /or exacerbate diseases such as ischemic heart disease, hypertension, arthriti s and

h ffi 'd . b I' RO 8) 88 cataract throug e ect on OX I atlve meta 0 Ism . -. .

Other dietary ingrediellts Spices and loxic injwy

Goud VK el al9 1 evaluated the effec ts of dictary turmeri c (0.5-10%) on hepatic xenobiotic metabol ising enzymes in rats. Ary l hydrocarbon hydroxylase, UDP glucuronyl transferase and glutathion-S-transferase were found to be increased after four weeks of fcedin g. Further resu lts indicated an tiox idant and detox ifyi ng propert ies of turmeric . Turmer ic contains curcumin as acti ve ant imutagen and thi s widely used spice wou ld proba bly mitigate the effects of several dietary carcinogens.

Dietary./ibre and tox ic injwy

Fry ing, grilling or roasting meat, fi sh and other foods have been shown to release heterocycl ic ami nes which are high ly poten t mutagens and potential carc inogens'12. The fr ied or flame-grilled foods are 10-fold more mu tagen ic than boiled or baked foods The exten t of thei r formation depends on cooking tcm perature and method,q

A high incidence of colon cancer has been re ported in individuals on low fiber andlor high-fat diet. Wheat bran is effecti ve in decreasing the mutagenic activity of II1lIn an feces'J4. Dietary fiber protects thc large intestine li'om DNA hind ing of the mutagenic amine an the cooked fo od b~

di luti ng thc intest inal content and decreas ing transit lime'''' , Dietary fibe r also plays an important ro le in the mctnhol islll and di spos it ion of lipids and fat s and thus reduces the incidence of MNNG- induced colon cancer""'

Alcohol and nUlriliul7

Ethanol is oxid ised in li ver microsomes by the ethanol inducib le cytochrome P'+502F I resulting In ..?l hanol to lerance and se lective hepatic pCrl venular <.I a III age Furthennore P4502E I acti vate va rious xenohiutics cxplaini ng the increased susceptibili ty of th heavy <.Irin!..er to the tox icity of anesthetics, analges ics, ind ustrial solve nts

LALL et al.: NUTRJTlON & TOXIC INJURY 113

and other chemical carcinogens. Induction of microsomal enzymes also contributes to vitamin A depletion. The hepatotoxicity of alcohol increases due to increased acetaldehyde generation from ethanol. There is formation of protein adducts, glutathione depletion, and lipid peroxidation. 1n baboons s-adenosyl-L-methionine attenuates the ethanol-induced glutathione depletion and associated mitochondrial lesions97

.

Some of direct hepatotoxic effects are linked to redox changes produced by reduced nicotinamide adenine dinuleotide (NADH) generated via the alcohol dehydrogenase (ADH) pathway. To alleviate adverse effects, and to correct problems of night- blindness and sexual inadequacies, the alcoholic patients may have vitamin A and choline supplementaion. S4ch therapy, however is complicated by the fact that in excessive amounts Vit.A is hepatotoxic, and massive doses of choline also exert some toxic effects . Acetaldehyde generated during ethanol metabolism impairs hepatic oxygen utilization, induces antibody production, and affects DNA repair. It also enhances pyridorine and perhaps to late degradation and stimulates collagen production 98 .

Phosphatidylcholine, purified from polyunsaturated lecithin was discovered to oppose the ethanol-induced fibrosis by decreasing the activation of lipocytes in transitional cells, and possibly also by stimulating collagenase activity, an effect for which dilinoleoylphosphatidylcholine, its major phospholipid species, was found to be responsible99

.

Drugs and nutrition The type of food and its ingredients like proteins, lipids

and carbohydrates have been shown to affect the bioavailability of drugs·lDl

. Food as such may influence not only the absorption but also the first pass metabolism of drugs in the gut and liver l02

. The alteration of the carbohydrate and protein ratio in the diet may change the elimination rate of certain drugs 103. The absorption of theophylline has been reported to decrease with high fat diet in rabbits lO4

,105.

The liver plays a major role in drug disposition (phase I & II) in the body. Membrane-bound mixed function oxidative enzymes, system plays a major role in metabolizing drugs. Microsomal oxidation in animals fed with protein-deficient diets is depressed, while the high protein and lipid diet help in activity restoring the metabolism 106. Similar findings have been reported in patients with protein energy malnutrition. Further microsomal oxidation is impaired by total parenteral nutrition and that this effect is absent when energy source from carbohydrates is changed to a conventional amino acid solution with lipid. Peripheral parenteral nutrition appears to increase antipyrine clearance lO6

•

The behavioral effects of chlorpromazine and haloperidol are less persistent in under nourished as compared to well-nourished rats, possibly due to differences in drug distribution and elimination 107.

There is at present enough evidence to support monitoring plasma drug concentrations' in malnourished

children, particularly for those drugs which have dose­dependent kinetics and narrow margins of safety.

The metabolism and disposition of xenobiotics seems to vary widely in children with protein-energy malnutrjtion. Therapeutic inadequacies and toxicities need careful evaluation in malnourished children 108 .

Food as toxicant A number of carcinogenic and mutagenic substances are

present in the diet, certain specific chemical moities in plants have been to shown to be toxic to experimental animals and to human beings.

Safroles, estragoles, methyleugenols and re lated . d . d 109 compounds are carcinogens an mutagens In ro ents .

Black pepper contains safroles which are toxic at a dose of 4 mglkg per day when given for 3 months" O

.

Hydrozines are present in edible mushrooms are carcinogenic 111 , 112 . Psora len derivat ives present in figs celery and parsley when acti vated by sunlight can damage DNA" 3

. "5

.

The potato contains glycoalkaloids ( 15 mg/200g) wh ich are strong cholinesterase inhibitors and poss ible terato­gens" 6

. "7

.

Quinones in diet get converted' to semiquinone radica ls, which react directly with DNA or participate in a redox

f 'd d' I . 0 118 11 9 M cycle 0 superoxi e ra Ica generation 2 '. any dietary coffee contains several natural mutagens including (alcohol derivatives mg of caffeine can inhibit DNA repair system, can increase tumor yield and cause birth defects in

. . I 120· 122 A .. b h.. h expenmental amma s . SSOClation e.vveen eavy coffet; drinking with cancer of ovary, bladder, pancreas and large bowel is reported 123.

Phenols can spontaneously autoxidize to quinones generating hydrogen peroxide (H 20 2) . Phenol derivative is a potent promoter of carcinogenesis inducer of DNA damage, a likely active metabolite of the carcinogen

118 d . .. k 124 benzene ,an also tOXIC agent In cigarette smo e .

Cocoa powder and tea is a source oftheobromines which is genotoxic and may potentiate DNA damage ' by various other carcinogens and cause testicular atrophy and spermatogenic cell abnormalities in rats m . Pyrroli zidine alkaloids which is present in many plant species are consumed by humans, ·as herbal tea and occasionally in honey. These alkaloids are carcinogenic, mutagenic and teratogen ic 126. 127 . Allyl isothiocyanate are present in oi l of mustard seeds and have been shown to cause chromosomal aberration in hamster cells at low concentration 128 and to be induce carcinogenesis in rats 129. Flava beans contain toxins, vicine and convicine, which can cause hemolytic anaemia in persons with G6PD deficiency. Gossupol , a major toxin in cotton seeds causes abnormal sperm count and male sterility. Aflatoxin present in food grains infected with fungus can cause carcinoma of liver in human beings. Mold

. d fi d . . . d . 130. 13 I contaminate 00 IS carcinogenic an mutagel1lc Nitrites and nitrosamines which are derived from nitrates present in diet, constituting of lettuce, spinach, radishes, and rhubarb are carcinogenic l32. Sterc:ulic acid and malvalic acid are toxic cyclopropenoid fatty acids present in seeds of cotton, okra and durian. These may also contaminate diet

114 INDIAN J EXP BIOL, FEBRUARY 1999

through milk, of animals fed on cotton seeds. These are Imown carcinogenic in ' rodents 133. Alfalfa sprouts contain canavanine and can cause severe SLE like syndrome in monkeys \34.

Epidemiological studies are suggestive of association of high fat intake and colon and breast cancer IJ5

-I37

.

Thus human is predisposed to numerous toxic compounds through diet. The detoxifying machinery present in the body together with several anticarcinogenic substances in the food normally keep the balance and protect from ill effects .

Conclusion

Man is exposed to a number of toxic substances in the environment as well as to toxic metabolits and ROS generated within the body. These would have quickly proven fatal if the biological defense systems were not developed to protect the organisms from the ir dan;.aging effects. The individual components of these biological defense systems are expended in their protective role:s and need replenishment by various constituents of the diet. Thus, almost all the ingredients of the diet including carbohydrates, proteins, lipids, vitamins, trace elements, spices, and dietary fibers play an important role in detoxication and in prevention of oxygen free radica l and toxic chemical induced pathogenes is of disease processes. The nutrition significantly affects the biotransformation of the drugs in the body, thereby causing variations in drug response . In addition to the protective role of d iet in toxic injuries, role of certain chemica l moieties in the diet act as tox icants .

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