PRINCIPLES OF TOXICOLOGY

70 BIOTRANSFORMATION: A BALANCE BETWEEN BIOACTIVATION AND DETOXIFICATION
microsomal oxidizing enzyme, these enzymes are not subject to extensive induction (see discussion
later).
Monoamine oxidases, which are usually mitochondrial in location, oxidize by electron transfer to
a 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 in
toxicities 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), which
leads to Parkinson’s syndrome, is bioactivated by monoamine oxidase B (a form selectively inhibited
by deprenyl and located in serotonergic neurons in the brain). Environmental compounds or drugs that
are also tetrahydropyridines have been speculated to be causative agents in Parkinson’s disease in the
elderly.
Phase I; Hydrolyses
Figure 3.9 The cytochrome P450 oxidation cycle.
Hydrolysis reactions are catalyzed by esterases and amidases. While both can be microsomal, esterases
are predominantly cytosolic in location. Hydrolysis of amides and esters produces two reactive centers,
TABLE 3.5 Compounds Metabolized by the Flavin-Containing Monooxygenases
Heteroatom Class Examples
Nitrogen Tertiary amine N-Dimethylaniline, imipramine, amitryptyline
Secondary amine N-Methylaniline, desipramine, nortryptyline
Sulfur Thiocarbamides Thiourea, propylthiouracil, methimazole
Thioamides Thioacetamide
Thiols Dithiothreitol, β-mercaptoethanol
Sulfides Dimethylsulfide