Lecture 16: Plant Toxin Flashcards Preview

NST 110 > Lecture 16: Plant Toxin > Flashcards

Flashcards in Lecture 16: Plant Toxin Deck (23):
1

Goitrogens

goiter producing agents

2

Goiter

- a swelling of thyroid gland

- can be caused by iodine deficiency, which leads to hypothyroidisam,
(hyperplasia of thyroid to compensate for decreased efficacy).

- resulted from an autoimmune disease, Hashimoto disease, in which the thyroid gland is gradually destroyed. This also results in hypothyroidism.

- resulted from another autoimmune disease, Grave’s disease, in which
autoantibodies activate TSH receptor and stimulate thyroid growth. This
causes hyperthyroidism.

3

thyroid hormones

The thyroid hormones act on nearly every cell in the body:
1. increase the basal metabolic rate,
2. affect protein synthesis,
3. help regulate long bone growth (synergy with growth hormone),
4. neuronal maturation
5. increase the body's sensitivity to catecholamines (such as adrenaline) by permissiveness.
6. regulate protein, fat, and carbohydrate metabolism, affecting how human cells use energetic compounds.
7. stimulate vitamin metabolism.
8. heat generation
Thyroid hormones (T4 and T3) are produced by the follicular cells of the thyroid gland and are regulated by Thyroid-stimulating hormone (TSH) made by the thyrotrophs of the anterior pituitary gland. The effects of T4 in vivo are mediated via T3 (T4 is converted to T3 in target tissues; T3 is 3- to 5- fold more active than T4).

4

Other Goitrogens

A. iodide trapping (blocked by thiocyanates (SCN-), nitrate (NO3-); SCN- is a detox
product of CN-)
B. organification (inhibited by goitrin in Brassica plants)
C. proteolysis (blocked by excess iodide)
D. deactivation (TCDD, PB can induce UDP-GT;UDP-glucuronyltransferase)
E. peripheral activation (inhibited by R#3)
SCN-, NO3-, goitrin lead to hypoactivity of thyroid—less activity of thyroid.
Excess iodide can also inhibit proteolysis ; deactivation via UDP-GT can be
enhanced by induction of UDP-GT by TCDD, PB deactivate thyroid
MDI—inhibited by R#3 produces hyperactive thyroid

5

Hypothyroidism symptoms:

-Female infertility, any kind of problems with menstrual cycles
-Poor muscle tone (muscle hypotonia)
-Fatigue
-Hyperprolactinemia and galactorrhea
-Elevated serum cholesterol
-Cold intolerance, increased sensitivity to cold
-Constipation
-Rapid thoughts
-Depression
-Muscle cramps and joint pain
-Thin, brittle fingernails
-Decreased sweating
-Dry, itchy skin
-Weight gain and water retention
-Bradycardia (low heart rate – fewer than sixty beats per minute)

6

substances that suppress the function of the thyroid gland by interfering with iodine uptake cause an enlargement of the thyroid.

Soybeans (and soybean products such as tofu)
Pine nuts
Peanuts
Millet
Strawberries
Pears
Peaches
Spinach
Bamboo shoots
Radishes
Horseradish
Vegetables in the genus Brassica

7

Thyroid Hormone Receptor can be a target for lowering plasma lipids and
weight loss therapy

-Thyroid Hormone reduces plasma cholesterol and triglyceride levels and increases energy expenditure. But it also causes tachycardia.
-The regulation of lipid metabolism is exerted in liver, whereas
the modulation of heart beat is occurred in heart.
Thyroid Hormone Receptors:

a1: widely expressed, especially in cardiac and skeletal muscle

a2: widely expressed, but cannot binds to hormones

b1: Brain, Liver, Kidney

b2: Hypothalamus and pituitary

8

Cyanogenic glycosides

Cyanogenic glycosides are produced by plants as a defense mechanism in bitter almonds, choke cherry seeds, apple seeds, and cassava (Africa), e.g. amygdalin

Cyanide (CN-) toxicity:
-Acute toxicity: blocks e- transport by blocking cytochrome oxidase in mitochondria (CN---Fe+3 (ferric iron of cyt-ox))
-Chronic tox: metabolism of cyanide to SCN- (thiocyanate)

9

cassava and -SCN

People who eat cassava have higher SCN- levels in blood and higher incidence of goiter and thyroid cancer.
If sulfur nutriture is sufficient (cysteine), there are less serious chronic effects.
In cysteine (sulfur) deficiency, more serious chronic effects occur.
tropical ataxic neuropathy—optic atrophy, inability to walk properly
tropical amblyopia—optic atrophy

Mode of action: OCN- (cyanate) formation from decreased thiosulfate (S2O3- ) leads to inhibition of glutathione reductase and increased oxidative stress. Cyanate has
neurodegenerative effects.

10

Ricin:

Some legumes are highly toxic: Castor Bean
Active compound is ricin from Ricinus communis (LD is 2-5 uncooked beans)—castor oil is from steam distillation (protein toxins are destroyed)

11

mechanism of Ricin

Caster bean --> pre-ricin--> cleavage ---> A/B complex (via dithiol linkage) A-S-S-B (active Ricin) --> B chain binds galactose moieties on membrane surface --> enoxytosis of B chain (along with A-chain) --> A-chain is a glycosidase that removes adenine from 28s ribosomal RNA (deactivates ribosome--> blocks protein synthesis

12

Licorice

Active compound: glycyrrhetinic acid mimics aldosterone action, an agonist for the mineralocorticoid receptor (MR)?
used as sweetening agent
causes Na+, water retention, hypertension, increased blood pressure

13

Aldosterone

Aldosterone is a hormone that increases the reabsorption of sodium and water and the release (secretion) of potassium in the kidneys. This increases blood volume and, therefore, increases blood pressure. Many drugs, such as spironolactone, lower blood pressure by blocking the aldosterone receptor.

Aldosterone is a steroid hormone (mineralocorticoid family) produced by the outer-section (zona glomerulosa) of the adrenal cortex in the adrenal gland, and acts on the distal tubules and collecting ducts of the kidney.

14

Glycyrrhetinic acid

- the affinity of glycyrrhetinic acid for mineralocorticoid receptors is negligibly low.
-Secondly, liquorice has no mineralocorticoid effect in adrenalectomized rats or in patients with Addison's disease (low cortisol levels).
-the mineralocorticoid effect of glycyrrhetinic acid was restored when liquorice was given together with 11ß-hydroxy-glucocorticosteroids to animals or humans without adrenal function,
-----> suggesting an interaction between glycyrrhetinic acid and glucocorticoids

Inhibition of 11-hydroxysteroid dehydrogenase type I causes decreased levels of active glucocorticoids

Inhibition of 11-hydroxysteroid dehydrogenase type II causes increased levels of active glucocorticoids

15

Corticosteroids

are a class of steroid hormones that are produced in the adrenal cortex

16

Glucocorticoids

(cortisol, corticosterone) control carbohydrate, fat and protein
metabolism, are anti-inflammatory, required for lung development and affect CNS (reduce memory and increase anxiety and cause depression),

17

Mineralocorticoids

(aldosterone) control electrolyte and water levels, mainly by promoting sodium retention in the kidney.

18

mineralocorticoid action in renal cells of the cortical collecting duct

1. Aldosterone activates apical
epithelial sodium channel
(ENaC) and the basolateral
sodium–potassium (Na/K) ATPase
genes, which lead to
sodium (Na+) reabsorption and
potassium (K+) excretion

2. Cortisol, circulates at a 100–
1000-fold higher levels than
aldosterone. But in kidney
11-HSD II converts active
cortisol to inactive cortisone.

3. Glycyrrhetinic acid inhibits the
11ß-HSD2 and therefore leads to
an unrestricted activation of the MR
by cortisol.

19

Another Action of Glycyrrhetinic Acid

Glycyrrhetinic acid inhibits 15-hydroxyprostaglandin dehydrogenase that metabolize the prostaglandins PGE-2 and PGF-2α to their respective inactive 15 keto-13,14-dihydro metabolites. Thus, glycyrrhetinic acid treatment can accumulate PGE-2 and PGF-2alpha.

20

Caffeine

--readily absorbed and metabolized quickly and causes CNS stimulation, diuresis, increased heart rate and blood pressure

at high doses >500 mg/person, can cause nervousness, irritability, cardiac arrhythmia

caffeine might affect cell growth (therefore ADI is lower for reproductive-age women and children)

caffeine and stress
- Pregnant women are suggested to not drink a lot of coffee during pregnancy because it may have an affect on cell growth

21

Mechanism of Caffeine

Caffeine is an antagonist of adenosine receptor and can cross blood-brain barrier

-Adenosine, a neurotransmitter, has an inhibitory effect on CNS. Caffeine inhibits adenosine effects by binding to the same receptors, and therefore effectively blocking adenosine receptors in the CNS (Adenosine 2A R). This reduction in adenosine activity leads to increased activity of the dopamine and glutamate.
-Caffenine inhibits Adenosine 1 R in heart, which results in an increased heart rate.

22

Metabolism of Caffeine

* Paraxanthine (84%): Has the effect of increasing lipolysis, leading to elevated glycerol
and free fatty acid levels in the blood plasma.

* Theobromine (12%): Dilates blood vessels, causes anxiety and sleepless and increases urine volume. Theobromine is also the principal alkaloid in cocoa, and therefore chocolate.

* Theophylline (4%): Relaxes smooth muscles of the bronchi, and is used to treat asthma. The therapeutic dose of theophylline, however, is many times greater than the levels attained from caffeine metabolism.

All three antagonize adenosine R. Each of these metabolites can be further metabolized and then excreted in the urine.

23

Caffeine and 3 metabolites

Caffeine and its three metabolites also inhibit cAMP-phosphodiesterase (cAMP-PDE), which converts cyclic AMP (cAMP) in cells to its noncyclic form (AMP), allowing cAMP to build up in cells.
--> caffein inhibits cAMP-PDE--> cAMP increased --> PKA activated --> hormone-sensitive lipase activated --> hydrolyze triacyglcerol to fatty acids and glycerol (lipolysis)