PRINCIPLES OF TOXICOLOGY - Biology East Borneo

82 BIOTRANSFORMATION: A BALANCE BETWEEN BIOACTIVATION AND DETOXIFICATIONMaturation The age of a rat can also cause changes in its complement of drug metabolizing enzymes.Old age decreases the cytochrome P450 concentration and activity, particularly in the male. Of thephase II enzymes, a decline in sulfotransferase activity is apparent. Glutathione S-transferase appearsmarginally increased in old rats and lower in immature rats as compared to the mature adult. Neonatalanimals generally exhibit lower drug-metabolizing activities than adults (Table 3.10).In humans, the activity of microsomal and perhaps nonmicrosomal xenobiotic-metabolizingenzymes is low in premature and neonatal infants. The effective glucuronidation of the bulky-typemolecules, (e.g., morphine and chloramphenicol) appears to develop much later than does that for theplanar phenol-type compounds. The activity of microsomal enzymes in neonates can be induced.Although there is evidence that the elderly have a decreased rate of hepatic microsomal metabolismof some drugs, the clinical importance of this is not clear because drug clearance remains unchangedas a consequence of changes in the volume of distribution of many drugs. The metabolism of manydrugs and xenobiotic chemicals is fastest in adolescents.Environment Human chemical drug metabolism can be influenced by the environment and diet. Alldiets contain naturally occurring nutrients and may also contain pesticide residues and food additivesthat are capable of altering the activity of chemical/drug-metabolizing enzymes. Among the morerecent nutrient interactions is an inhibition of cytochrome P450 3A by grapefruit juice flavonoids,naringin and quercetin. Other flavonoids (catechin, myricetin, rutin, etc.) are able to induce phase IIenzymes and protect against bioactivated intermediates (see discussion below).Even the quality of the diet can have an effect. Protein deficiency or diets deficient in essential fattyacids or certain vitamins (e.g., A, C, E) can decrease xenobiotic metabolism. Supplementation of dietswith these nutrients (e.g., high protein) can increase chemical metabolism above normal. Administrationof drugs and exposure to toxic compounds in burned carbonaceous material such as cigarettesmoke and charcoal-broiled foods are among the best known modifiers of xenobiotic metabolizingcapabilities.It is evident from the foregoing illustrations concerning the complex mixture of factors responsiblefor variations in xenobiotic metabolism that while a basic understanding of chemical metabolism canprovide guidelines, prediction of actual situations is infinitely more difficult. While genetic differencesbetween species may be obvious, subtle differences in physiology and diet all tend to confoundextrapolations between experimental animals and, more critically, between experimental animalmodels and humans. These differences may even confound extrapolation between subgroups withinthe human population.TABLE 3.10 Influence of Maturity on Rat Xenobiotic-Metabolizing Enzymes aPhase IPhase IIpNA UGTAge Gender and Strain P450 deM GT1 GT2 GST ST(vs. Young Adult)Immature Male Sprague–Dawley b 1.00 1.05 0.50 0.90 — —Female Sprague–Dawley b 1.40 1.00 0.55 1.05 — —Old Male Fischer 0.65 0.70 0.95 1.00 1.10 0.60Female Fischer 0.90 0.80 1.00 1.10 1.05 0.70a Abbreviations: p NA deM = p-nitroanisole demethylase; UGT = UDP-glucuronosyltransferase (two isozymes; GT1 and GT2);GST = glutathione S-transferase; ST = sulfotransferase.b Chengelis CP, Xenobiotica 18: 1225 (1988).