Toxicology
The acute toxicities of Trp-P-1 and Trp-P-2 are toxic to animals: LD50 (intragastric intubation) of Trp-P-1 are 200 mg/kg in mice, 380 mg/kg in Syrian golden hamsters, and 100 mg/kg in rats. Trp-P-2 is slightly more toxic than Trp-P-1. Animals that received over the LD50 usually died in convulsions within an hour. Trp-P-1 and Trp-P-2 induce a local inflammatory reaction when injected subcutaneously. The early work on the isolation and production of these substances was based on their mutagenicity. They are also minor components of fried beef. Several other mutagens of this class are also present in cooked meat. Beef extracts, which contain IQ and MeIQx, are metabolically converted to active mutagens by liver tissue from several animal species and humans. Although these substances are highly potent mutagens, they are fairly weak carcinogens in rats. Following the mutagenicity studies on these pyrolysates the carcinogenicity of tryptophan (Trp-P-1 and Trp-P-2) and glutamine (Glu-P-1) was demonstrated using animals such as rats, hamsters, and mice. For
example, a high percentage of tumor incidences were observed in mice fed a
diet containing Trp-P-1 or Trp-P-2. High incidences of hepatoma were found
in mice treated with Trp-P-1, Trp-P-2, Glu-P-1, and Glu-P-2. Female mice
were more sensitive than males.
Some PAAs, such as IQ and MeIQ, exhibit strong mutagenic activity.
Although Trp-P-1, Trp-P-2, and Glu-P-1 are highly mutagenic—being more
mutagenic than the well-known carcinogen aflatoxin B1, they are much less
carcinogenic than aflatoxin B1. This may be the result of their high initiating
activities but low promoting activities. Carcinogenicity of these potent
Polycyclic Aromatic Amines (PAA)mutagens is accounted for by hypothesizing that Polycyclic Aromatic Amines (PAA)can be metabolically
activated by humans both through N-oxidation and O-acetylation,
to produce highly reactive metabolites that form DNA adducts. The human
enzyme activities for some substrates are comparable to those of the rat, a
species that readily develops tumors when fed these Polycyclic Aromatic Amines (PAA)as part of the daily diet. Therefore, these PAAs should be regarded as potential human
carcinogens.
