Role of Phytoconstituents in Modulating Xenobiotic Metabolism
Pp. 160-192 (33)
Harsimran Kaur, Sandeep Kaur, Satwinderjeet Kaur and Paramjeet Kaur
Contaminant-induced harmful effects are a global concern. Liver is the main
site of xenobiotic metabolism and plays a vital role in averting accumulation of a wide
range of compounds by converting them into a form suitable for elimination. Phase I
drug metabolizing enzymes, primarily cytochrome P450s carry out bioactivation of
carcinogens, thus converting them into electrophilic species which are genotoxic and
cytotoxic. These reactive intermediates form protein adducts and induce DNA and
RNA damage. Phase II drug metabolizing enzymes, such as glutathione-S-transferases,
UDP-glucuronosyl transferases, sulfotransferases and N-acetyltransferases detoxify the
reactive electrophilic species by conjugating these hydrophobic intermediates to a
water-soluble group, thus masking their reactive nature and allowing subsequent
excretion. Beneficial effects of natural dietary compounds in detoxification and
elimination have been demonstrated in various studies. They have been reported to be
effective in inhibiting chemically-induced carcinogenesis. Phytochemicals are known
to influence the biotransformation of xenobiotics and may play an important role in
reducing their toxicity and carcinogenicity. Indoles, isothiocyanates, allium
organosulfur compounds, flavonoids, phenolic acids, terpenoids and psoralens may
alter the levels of Phase I and Phase II drug metabolizing enzymes by affecting the
transcriptional rates of their genes, the turnover rates of specific mRNAs or enzymes or
the enzyme activity by inhibitory or stimulatory actions. Agents that preferentially
activate Phase II over Phase I enzymes are considered as promising chemopreventives.
Phase I metabolism involves oxidation, reduction or hydrolysis reactions via
cytochrome P450 enzymes and lead to the conversion of drugs to more polar (water
soluble) active metabolites by unmasking or inserting a polar functional group such as
-OH, -SH and –NH2. Xenobiotics metabolized via Phase I reactions have longer halflives.
Phase II metabolism involves conjugation reactions such as glucuronidation,
acetylation and sulfation. Conjugation reactions increase water solubility of drug by
adding a polar moiety thus converting them into water soluble inactive metabolites.
The present book chapter discusses the interaction between phytochemicals and xenobiotic metabolizing enzymes in detoxification of harmful exogenous compounds
which have been implicated in carcinogenesis.
Aflatoxin B1, Aldoketoreductase, Benzo[a]pyrene, Carbon
Tetrachloride, Cytochrome P450 Monooxygenase, 7, 12-dimethylbenz (a)
anthracene, 1, 2-dimethyl hydrazine, Epoxide Hydrolase, Flavin Containing
monooxygenase, Gamma Glutamyl Transferase, Glucose-6-phosphate dehydrogenase,
Glutathione Peroxidase, Glutathione Reductase, Glutathione-Stransferase,
Hamster Buccal Pouch, Hepatocarcinogenesis, Malondialdehyde,
Nuclear Factor-like 2/Antioxidant Response Element, Phase I & II, Polycyclic
Aromatic Hydrocarbon, Xenobiotics.
Department of Botany, Khalsa College, Amritsar, India.