PRINCIPLES OF TOXICOLOGY - Biology East Borneo

70 BIOTRANSFORMATION: A BALANCE BETWEEN BIOACTIVATION AND DETOXIFICATIONFigure 3.9 The cytochrome P450 oxidation cycle.microsomal oxidizing enzyme, these enzymes are not subject to extensive induction (see discussionlater).Monoamine oxidases, which are usually mitochondrial in location, oxidize by electron transfer toa flavin group. Monoamine oxidases are responsible for the normal metabolism of neurotransmitters,and exposure to agents, which are also metabolized by this enzyme, (e.g., tyramine) can result intoxicities or pharmacological effects arising from accumulation of the unmetabolized neurotransmitter.A neurotoxin of much recent interest, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), whichleads to Parkinson’s syndrome, is bioactivated by monoamine oxidase B (a form selectively inhibitedby deprenyl and located in serotonergic neurons in the brain). Environmental compounds or drugs thatare also tetrahydropyridines have been speculated to be causative agents in Parkinson’s disease in theelderly.Phase I; HydrolysesHydrolysis reactions are catalyzed by esterases and amidases. While both can be microsomal, esterasesare predominantly cytosolic in location. Hydrolysis of amides and esters produces two reactive centers,TABLE 3.5 Compounds Metabolized by the Flavin-Containing MonooxygenasesHeteroatom Class ExamplesNitrogen Tertiary amine N-Dimethylaniline, imipramine, amitryptylineSecondary amine N-Methylaniline, desipramine, nortryptylineSulfur Thiocarbamides Thiourea, propylthiouracil, methimazoleThioamidesThioacetamideThiolsDithiothreitol, β-mercaptoethanolSulfidesDimethylsulfide