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A Canary's Eye View — Metabolic Basis
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Detoxification –
study notes in progress
(items particularly applicable to me are in orange)

NOTE ON TESTS:

  • Many of these functions are measured in the GSDL Detoxification Profile. See my results from that test on 28 November 2001.
  • In addition, the Genovations DetoxiGenomic Profile identifies polymorphisms (SNPs) in genes responsible for some of these functions. I had this test performed 22 June 2006; see my results from the DetoxiGenomic Profile.

Liver Phase I: functionalization (oxidation, reduction or hydrolysis reactions, increasing solubility of the substrate)

P450 Enzymes use oxygen to process many endogenous and exogenous subtances, adding a reactive group, such as hydroxyl radical, to the molecule being processed in order to enable Phase II to deal with it.

Pathological detoxifiers / Liver backlog

  • Phase I produces more than Phase II can handle.
    • highly sensitive to fumes eg paints, perfumes
    • react adversely to various pharmaceutical drugs
    • may react to drinking caffeine
  • So should I try to inhibit Phase I?
    • "May find it useful to include grapefruit juice in their diet" says Kimber
      • grapefruit juice inhibits CYP3A4 for up to 72 hours (Julian Whitaker says all CYP3As, October 2002 Health & Healing, p.4)
    • for other inhibitors see P450 Perturbation
  • MiDobs on the AMALGAM list says "Someone who (still/now) has normal Phase I but poor Phase II sulfation, as a result of mercury poisoning, can take glucosamine sulfate while dealing with the mercury." [That's an interesting possibility, how can I check it?](see directions for access)
    • from MiDobs@INTERNETWIS.COM
    • message-ID: <199902281552.SM00141@default>
    • Sun, 28 Feb 1999 14:50:18 -0800
  • In "Looking at the Patient," (no longer on the Web) Han van den Braak mentioned that mineral deficiency commonly underlies "liver backlog" where Phase I is more active than Phase II.

Liver Phase II – Conjugation (biotransformation of a lipophilic compound, by combining it with another substance, to a water-soluble compound able to be excreted)

Processes (Cofactors must be replenished through dietary sources)

Sulfation

Acetylation

Glucuronidation

  • glucuronic acid
  • commonly induced by multi-functional inducers
  • can be supplemented with Calcium D-Glucarate
  • is slower than sulfation

Acylation (peptide conjugation)
The amino acids glycine, taurine, glutamine, arginine, and ornithine combine with toxins to neutralize and eliminate them.

  • Most common: glycine (the one Great Smokies tests)
    • the most important route of detoxification for
      • endogenous acids.
      • many xenobiotic carboxylic acids
      • salicylates
      • benzoate
    • "However, the first reaction of glycine conjugation in some cases is reported to involve a class of active intermediates implicated in toxicity."
      • (from Reaction Mechanism of Amino Acid Conjugation and Determination of the Structure. Fumiyo KASUYA ( Faculty of Pharm aceutical Sciences, Kobe-gakuin University ( 518, Arise, Ikawadani, Nishi-ku, Kobe 651-2180, Japan) in J. Mass Spectrom. Soc. Jpn., 49(3), 89-95, 2001. English abstract )
    • Rate-limiting enzyme: the medium chain acyl-CoA synthetase catalyzing the initial reaction of glycine conjugation. In addition, the stability of acyl-CoAs may be a determining factor.
  • The amino acid conjugation system can become damaged by hepatitis, alcoholic liver disorders, carcinomas, chronic arthritis, hypothyroidism, toxemia of pregnancy, and excessive chemical exposures.

Glutathione conjugation (mercapturic acid synthesis)

  • glutathione
  • commonly induced by multi-functional inducers
  • cofactors: Vitamin E, selenium
    • "The cooperation of Vitamin E and selenium produces the vital antioxidant peptide enzyme selenium-glutathione-peroxidase. Appears to help stimulate the production of antibodies, and may stimulate synthesis of protein." – Autism Center's Supplement Reference
    • I feel sick for a couple hours after taking Vitamin E and selenium; does this mean I have trouble making glutathione or using it? It's better since I stopped taking cranberry juice extract, but not gone. It's also better if I get out of my office. If I take vitamin E without selenium, it doesn't happen; also I can take selenium for a few days before it starts.
  • Necessary for regulating bone density [anabolism?]
  • detoxifies (breaks down) estrogens

Multi-Functional Induction: substances inducing multiple Phase II processes
(Mono-functional induction is listed with the process it induces)

  • rosemary (provokes a reaction)
  • soy (provokes a reaction)
  • cabbage
  • brussels sprouts (can't eat much)
  • Garlic oil (provokes a reaction)
  • acetaminophen (provokes a reaction) See Acetaminophen Poisoning.

Methylation - takes place in every cell in the body

Intestines

  • Sulfation and glucuronidation go on here too. Some xenoestrogens inhibit these processes.
  • Useful enzymes at tip of villi
    • "Phase III" anti-porter activity: an energy-dependent efflux pump, which pumps xenobiotics out of a cell, thereby decreasing the intracellular concentration of xenobiotics. See reference 15 at Liska
    • Cyp3A4
  • Counterproductive process: enterohepatic recirculation. Beta-glucoronidase bacteria remove conjugation moiety — glocuronosyl side chain — converting estrogens back to their original form and allowing them to reenter circulation.

Kidney

General Detox Info:

Conditions

Treatments

  • Herbs (These are mostly specific for the liver)
    • Silymarin - has been helping me
    • Artichoke (related to Silymarin) stimultes bile
    • Burdock
    • Dandelion (I believe I reacted to this when I tried it in '97.)
  • NAC (N-Acetylcysteine) "not everybody tolerates NAC well."— Steven Shackel
  • Flavonoids?
    • "Scientists at the University of Minnesota have found that the two primary chemical components in lupulin [from hops] — humulone and lupulune — stimulate the production of liver enzymes that metabolize toxins." Bobbi A. McRaie, "Hops: Food, Shade, Flavoring and a Pillow for Your Head." The Herb Companion, April/May 1992, p. 62. (I have found similar statements around the Web but no documentation as yet.)

Links

copyright © 2000 by Catherine Holmes Clark. Last updated 1 November 2005