Page 325 - Color Atlas of Biochemistry
P. 325
316 Tissues and organs
Biotransformations Most oxidation reactions are catalyzed by
cytochrome P450 systems (see p. 318).
Thebodyisconstantlytaking up foreign sub- These monooxygenases are induced by
stances (= xenobiotics)from foodorthrough their substrates and show wide specificity.
contact with the environment, via the skin The substrate-specific enzymes of the ste-
and lungs. These substances can be natural roid metabolism (see p. 376) are exceptions
in origin, or may have been synthetically pro- to this.
duced by humans. Many of these substances Phase II reactions (conjugate formation). Type
are toxic, particularly at high concentrations.
However, thebodyhas effectivemechanisms II reactions couple their substrates (bilirubin,
for inactivating and then excreting foreign steroid hormones, drugs, and products of
phase I reactions) via ester or amide bonds
substances through biotransformations. The
mechanisms of biotransformation are similar to highly polar negatively charged molecules.
Theenzymes involved aretransferases, and
to those with which endogenous substances
such as bile pigments and steroid hormones their products are known as conjugates.
The most common type of conjugate for-
are enzymatically converted. Biotransforma- mation is coupling with glucuronate (GlcUA)
tions mainly take place in the liver.
as an O-or N-glucuronide. The coenzyme for
the reaction is uridine diphosphate glucuro-
A. Biotransformations
nate, the “active glucuronate” (see p. 110).
Phase I reactions (interconversion reactions). Coupling with the polar glucuronate makes
Type I reactions introduce functional groups an apolar (hydrophobic) molecule more
into inert, apolar molecules or alter functional strongly polar, and it becomes suf ciently
groups that are already present. In many water-soluble and capable of being excreted.
cases, this is what first makes it possible for Example (3) shows the glucuronidation of
foreign substances to conjugate with polar tetrahydrocortisol, a metabolite of the gluco-
molecules via phase II reactions (see below). corticoid cortisol (see p. 374).
Phase I reactions usually reduce the biological The biosynthesis of sulfate esters with the
activity or toxicity of a substance (“detoxifica- help of phosphoadenosine phosphosulfate
tion”). However, some substances only be- (PAPS), the “active sulfate”, (see p. 110) and
come biologically active as a result of the amide formation with glycine and glutamine
interconversion reaction (see, for example, also play a role in conjugation. For example,
benzo[a]pyrene, p. 256) or become more toxic benzoic acid is conjugated with glycine to
after interconversion than the initial sub- form themoresoluble and less toxic hippuric
stance (“toxification”). acid (N-benzoylglycine; see p. 324).
Important phase I biotransformation reac- In contrast with unconjugated compounds,
tions include: theconjugates aremuch morewater-soluble
and capable of being excreted. The conjugates
• Hydrolytic cleavages of ether,ester,and
peptide bonds. Example (1)shows hydrol- are eliminated from the liver either by the
ysis of the painkiller acetylsalicylic acid. biliary route—i. e., by receptor-mediated ex-
• Oxidations. Hydroxylations, epoxide for- cretion into the bile—or by the renal route,
mation, sulfoxide formation, dealkylation, via the blood and kidneys by filtration.
deamination. For example, benzene is oxi-
dized into phenol, and toluene (methylben- Further information
zene) is oxidized into benzoic acid.
• Reductions. Reduction of carbonyl, azo-, or To detoxify heavy metals,the livercontains
nitro- compounds, dehalogenation. metallothioneins, a group of cysteine-rich pro-
• Methylations. Example (2) illustrates the teins with a high af nity for divalent metal
2+
2+
2+
2+
inactivation of the catecholamine norepi- ions such as Cd ,Cu ,Hg ,and Zn .These
nephrine by methylation of a phenolic OH metal ions also induce the formation of metal-
group (see p. 334). lothioneins via a special metal-regulating el-
• Desulfurations. Thereactions take placein ement (MRE) in the gene's promoter (see
the hepatocytes on the smooth endoplas- p. 244).
mic reticulum.
Koolman, Color Atlas of Biochemistry, 2nd edition © 2005 Thieme
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