Phase 1 Detoxification Pathway: A Delicate Balance

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The primary function of Phase I enzymatic activity is to either:

  • Bio-transform a toxic lipophilic compound directly to a more hydrophilic compound so it can be directly excreted in the kidneys. Though, Phase I usually results in only a small amount of direct hydrophilicity and excretion.
  • The bulk of Phase I enzymatic activity takes place in the form of altering unwanted compounds in a way as to either expose or introduce a functional group, such as: Carboxyl group (–COOH), hydroxyl group (– OH), amino group (-NH2), or sulfhydryl group/thiol (-SH).

In the phase 1 detoxification process a toxic chemical is converted into a less harmful chemical through various chemical reactions. These chemical reactions are known as:

  • oxidation
  • reduction
  • hydrolysis
  • hydration
  • dehalogenation

Cytochrome P450 Enzyme System

The liver phase 1 detoxification system is initiated through the P450 cytochrome system which essentially reduces the toxin to smaller fragments.

Phase I enzymes begin the detoxification process by chemically transforming lipid soluble compounds into water soluble compounds in preparation for phase II detoxification. The bulk of the phase I transformation reactions are performed by a family of enzymes called the cytochrome P450s (CYP450).

Humans have 57 genes and more than 59 pseudo-genes divided among 18 families of cytochrome CYP450 genes and 43 subfamilies.

The activity of the various cytochrome CYP450 enzymes vary significantly from one individual to another based on genetics, the individual’s level of exposure to chemical toxins, and his or her nutritional status.   Phase 1 is utterly dependent on the cytochrome P4 50 enzymes whose speed of metabolism is in turn affected by things like genetics, exercise and the presence or absence of certain substances/supplements in the diet that can either speed them up (induce them) or slow them down (inhibit them).

CYP450s are the major enzymes involved in drug metabolism, accounting for about 75% of the total metabolism.  Most drugs undergo deactivation by CYP450s, either directly or by facilitated excretion from the body. Also, many substances are bio-activated by CYP450s to form their active compounds.

Most of the CYP enzymes in humans are found in the liver, the main organ involved in drug and toxin removal, but a remarkable amount is also found in the small intestine. Recent research shows that the cytochrome CYP450 enzyme systems are also found in other parts of the body, especially the brain cells.

Among the diverse human genes, several have been identified as particularly important in oxidative metabolism. They are:

  • CYP3A4 (the most important)
  • CYP2D6
  • CYP2C9
  • CYP2C19
  • CYP2E1
  • CYP2A6
  • CYP1A2

Although most of the CYP450s can be induced (the notable exception being 2D6), perhaps the most important in this regard is CYP3A4. 3A4 is the most prevalent CYP450 in the body, and metabolizes many substrates.

Bioactive Intermediates

This Phase I enzymatic alteration results in the unwanted compound now becoming a bio-activated intermediate. This gives rise to a more reactive and potentially more toxic and harmful substance than the original compound. Therefore, it must be acted upon rapidly by antioxidants and/or Phase II enzymes. 

During the phase 1 detoxification process, these bio-activated intermediaries are free radicals.  In a Phase I reaction, a cytochrome CYP450 enzyme uses oxygen to add a reactive group, such as a hydroxyl radical.

These bio-activated intermediaries (free radicals) can thus cause secondary damage to the cells.  If the body is low in either endogenous or exogenous antioxidants, then these free radicals are free to do damage to the body.  Therefore an adequate supply of various antioxidants are necessary to quench these free radicals to prevent tissue damage.

Antioxidants Needed to Quench Bioactive Intermediates

The following antioxidants have been used to quench these free radicals during this process:

  • glutathione
  • superoxide dismutase
  • beta carotene
  • vitamin D
  • vitamin E
  • selenium
  • zinc
  • N – acetyl cysteine
  • bioflavonoids and anthocyanidins

Nutrients Needed by CYP450 enzymes

The CYP450 enzymes require certain co-factors or nutrients in order to function properly.  These nutrients need to be supplied via the diet.  If there is a deficiency in any nutrient, then the CYP450 enzymes can be compromised and may not be properly conjugated by the Phase 2 detoxification process. 

The Table below list the necessary co-factors and nutrients needed by the CYP450 enzymes:

Phase 1 Nutrients

Nutrients
Copper
Flavonoids
Folic acid
Glutathione
Magnesium
Molybdenum
Vitamin B12
Vitamin B2
Vitamin B3
Vitamin B6
Vitamin C
Zinc

Induction or Activation of Phase 1 Enzymes

When the body is confronted with a high xenobiotic load, the Phase 1 enzymes involved in detoxifying this compound can be induced, leading to more enzymes being present and a faster rate of xenobiotic detoxification.  The Table below lists those substances that induce Phase 1 detoxification:

Inducers or Activators of Phase I Enzymes

CategorySubstance
Drugs
Alcohol
Nicotine in cigarettes smoked
Pentobarbital
Sulfonamides
Steroids
Barbiturates
Environmental toxins
Carbon tetrachloride
Exhaust fumes
Paint fumes
Dioxin
organophosphates
Pesticides
Foods
Cabbage, broccoli, and brussel sprouts
Charcoal broiled meats
High-protein diet
Oranges and tangerines but not grapefruits
Nutrients
Niacin
Vitamin B1
Vitamin B3 (niacin)
Vitamin B2 (riboflavin)
Vitamin B6
Vitamin B9 (Folic Acid)
Vitamin B12
Vitamin C
indole 3 carbinol
Limonene
Minerals
Magnesium
Iron
Lipotrophics
Cysteine
Methionine
Choline
Inositol
Herbs
Milk thistle
Sassafras
Caraway seeds
Dill seeds

Inhibition of Phase 1 Enzymes

In general, inhibition of detoxification is not desired.   The liver may become sluggish in the phase 1 detoxification cycle process and may not process toxins at a normal rate. This abnormal process may cause the accumulation of toxins in the blood stream. Substances that delay and slow down the phase 1 detoxification process are known as phase 1 inhibitors.

Many substances inhibit cytochrome CYP450. This situation can cause substantial problems as it makes toxins potentially more damaging because they remain in the body longer before detoxification.

Curcumin inhibits phase I while stimulating phase II. This effect can be very useful in preventing certain types of cancer.  Curcumin has been found to inhibit carcinogens, such as benzopyrene (found in charcoal-broiled meat), from inducing cancer in several animal models. It appears that the curcumin exerts its anti-carcinogenic activity by lowering the activation of carcinogens while increasing the detoxification of those that are activated.

Many substances inhibits cytochrome CYP450 as evidenced in the Table below:

Inhibitors of Phase 1 Detoxification Enzymes

CategorySubstance
Drugs
Benzodiazepine antidepressants
Antihistamines used for allergies
Cimetidine and other stomach acid secretion drugs
Ketoconazole
Sulfaphenazole
Foods
Grapefruit juice (naringenin)
Quercetin
Curcumin (turmeric)
Ellagitannin/Ellagic Acid (raspberries and berries and fruits)
Tumeric (curcumin)
Red chilli pepper (capsaicin)
Cloves (eugenol)
Epigallocatechin Gallate (EGCG) (green tea)
Sesamin (sesame seeds/oil)
Watercress
Substances
Silymarin (milk thistle)
Sulforaphane (cruciferous vegetables e.g. broccoli, cauliflower, kale etc)
Xanthohumol (hops/beer)
Other Inhibitors
Aging
Toxins from inappropriate bacteria in the intestines


Informational References:

Metabolic Rejuvenation Program by Douglas Laboratories


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