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

• requires Co-enzyme A

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.
  • see notes to Liska

Kidney

General Detox Info:

Conditions

• Mercury Poisoning
• Acetopminophen Poisoning
• Porphyrin Disorders

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

• The Liver of the Matter, by Linda Lazarides. Very useful.
• Detoxification Enzyme Systems, by DeAnn J. Liska, PhD (Altern Med Rev 1998;3(3):187-198)
• The Liver Detoxification Pathways, by Sandra Cabot, MD