SECTION 6.4

Inhibition

101

HC>

H7C30

OC,H7

.

v z / ~ H - ( p -

. / +H20

Regenerated

enzyme

hao

lN:

3 r

+H,0

O,

Phosphorylated

enzyme

Oxime-phosphonate

x y

Regenerated

enzyme

FIG U R E 6-10

Reactivation of alkylphosphorylated acetylcholinesterase. Spontaneous reactivation (dashed arrow) by water occurs at

an insignificant rate; however, loss of one isopropoxy group occurs at a much more rapid rate, yielding the “aged”

enzyme, which is resistant to reactivation. The regeneration of the enzyme by pralidoxime is shown at bottom.

normal cells are not affected by HCN because they contain

CN_-inactivating enzyme (rhodanese; see below). No ob-

jective evidence demonstrates any therapeutic value for

these compounds as anticancer agents. Their ingestion has

led to severe toxicity in some reported cases.

Nondietary sources of cyanide include sodium nitro-

prusside (a hypotensive agent), succinonitrile (an antide-

pressant agent), acrylonitrile (used in the plastic industry

and as a fumigant to kill dry-wood termites), and tobacco

smoke. Chronic exposure to cyanogenic compounds leads

to toxic manifestations such as demyelination, lesions of

the optic nerves, ataxia (failure of muscle coordination),

and depressed thyroid functions. This last effect arises

from accumulation of thiocyanate, the detoxified prod-

uct of cyanide in the body (see below). Thiocyanate in-

hibits the active uptake of iodide by the thyroid gland and,

therefore, the formation of thyroid hormones (Chapter 33).

Acute cyanide poisoning requires prompt and rapid

treatment. The biochemical basis for an effective mode

of treatment consists of creating a relatively nontoxic

porphyrin-ferric complex that can compete effectively

with cytochrome oxidase for binding the cyanide ion. This

is accomplished by the administration of nitrites (NaNC

>2

solution intravenously, and amylnitrite by inhalation),

which convert a portion of the normal oxygen-carrying

hemoglobin with divalent iron to oxidized hemoglobin

(i.e., methemoglobin with trivalent iron, which does

not transport oxygen). Methemoglobin binds cyanide

to form cyanomethemoglobin, whose formation is fa-

vored because of an excess of methemoglobin rela-

tive to cytochrome oxidase. This process may lead to

the restoration of normal cytochrome oxidase activity

(Figure 6-12). Cyanomethemoglobin is no more toxic than

methemoglobin and can be removed by normal processes

that degrade erythrocytes and by the reaction catalyzed

by rhodanese. Rhodanese (thiosulfatecyanide sulfurtrans-

ferase) catalyzes the reaction involving cyanide and thio-

sulfate to form thiocyanate:

SSO j' + enzyme = SOj- +

enzyme-S

Thiosulfate

Sulfite

Sulfur-substituted enzyme

Enzyme-S + CN_

—>

SCN-

+ enzyme

(Cyanide)

Thiocyanate