International Commission for Protection Against Environmental Mutagens and Carcinogens. The importance of the hydrophobic interaction in the mutagenicity of organic compounds.

The derivation of new QSAR and the review of published QSAR for the mutagenicity of a variety of chemicals acting on a variety of bacterial systems uncovers two classes of equations. 12 examples include a term for hydrophobicity and of these 12, 11 require activation either by S9 or cytosolic enzymes for the reduction of nitro compounds. There are 4 examples of direct-acting mutagens which do not require activation. Of these 4, 3 do not contain a term for hydrophobicity. The odd example is that of the sulfonate esters which do not require activation, but contain a term in log P. The hydrophobicity factor is not correlated with the type of bacteria used for the test.

Expanding the "Q" (quality) word.

It is time to move from quality individually defined--"excellence in clinical practice"--to quality socially defined--"excellence in clinical practice combined with accessibility, affordability, positive clinical outcomes and patient satisfaction." Only through such a systemic, matrix approach to quality can the mental health industry meet the needs of the patient population.

A QSAR investigation of the role of hydrophobicity in regulating mutagenicity in the Ames test: 1. Mutagenicity of aromatic and heteroaromatic amines in Salmonella typhimurium TA98 and TA100.

Quantitative structure-activity relationships (QSAR) have been derived for the mutagenic activity of 88 aromatic and heteroaromatic amines acting on Salmonella typhimurium TA98 + S9 and 67 amines acting on TA100 + S9. Mutagenic activity is linearly dependent on hydrophobicity, the energy of the highest occupied molecular orbital, and the energy of the lowest unoccupied molecular orbital of the amine. The dependence of mutagenic activity on hydrophobicity and electronic effects is nearly identical for TA98 and TA100. Mutagenic activity in TA98 is also found to depend on the size of the aromatic ring system. Different QSARs are derived for the mutagenic activity of hydrophilic amines (log P less than 1) acting on either TA98 or TA100. The mechanism of amine activation and reaction with DNA is considered in light of these findings.

Quantitative structure-activity relationship investigation of the role of hydrophobicity in regulating mutagenicity in the Ames test: 2. Mutagenicity of aromatic and heteroaromatic nitro compounds in Salmonella Typhimurium TA100.

A quantitative structure-activity relationship (QSAR) has been derived for the mutagenic activity of 117 aromatic and heteroaromatic nitro compounds acting on Salmonella typhimurium TA100. Relative mutagenic activity is bilin-early dependent on hydrophobicity, with an optimal log P of 5.44, and is linearly dependent on the energy of the lowest unoccupied molecular orbital of the nitro compound. The dependence of mutagenic activity on hydrophobicity and electronic effects is very similar for TA98 and TA100. Mutagenic activity in TA100 does not depend on the size of the aromatic ring system, as its does in TA9. The effect of the choice of assay organism, TA98 versus TA100, on nitroarene QSAR is seen to be similar to the effect previously found for aminoarenes. Lateral verification of QSARs is presented as a tool for establishing the significance of a new QSAR.

The structure-activity relationship of skin carcinogenicity of aromatic hydrocarbons and heterocycles.

From a study of 239 aromatic and heteroaromatic compounds causing skin cancer in mice, a quantitative structure-activity relationship has been derived. Carcinogenicity depends heavily on the relative hydrophobicity of the chemicals as defined by octanol/water partition coefficients (log P). It is also correlated with the energy of the highest occupied molecular orbital and the presence of substituents on the L and K regions of the carcinogen. The results are discussed in terms of the bay region concept for carcinogenic activity.

Structure-activity relationship of mutagenic aromatic and heteroaromatic nitro compounds. Correlation with molecular orbital energies and hydrophobicity.

A review of the literature yielded data on over 200 aromatic and heteroaromatic nitro compounds tested for mutagenicity in the Ames test using S. typhimurium TA98. From the data, a quantitative structure-activity relationship (QSAR) has been derived for 188 congeners. The main determinants of mutagenicity are the hydrophobicity (modeled by octanol/water partition coefficients) and the energies of the lowest unoccupied molecular orbitals calculated using the AM1 method. It is also shown that chemicals possessing three or more fused rings possess much greater mutagenic potency than compounds with one or two fused rings. Since the QSAR is based on a very wide range in structural variation, aromatic rings from benzene to coronene are included as well as many different types of heterocycles, it is a significant step toward a predictive toxicology of value in the design of less mutagenic bioactive compounds.

The role of hydrophobicity and electronic factors in regulating alcohol inhibition of cytochrome P-450-mediated aniline hydroxylation.

The role of hydrophobicity and electronic factors in regulating alcohol inhibition of cytochrome P-450-mediated aniline p-hydroxylation has been investigated by the formulation of quantitative structure-activity relationships. The activity of linear primary alcohols and unhindered linear secondary alcohols shows a linear dependence on log P, where P is the octanol-water partition coefficient. Hindered primary and secondary alcohols are less active than this relationship predicts. An equation describing the activity of both hindered and unhindered primary and secondary alcohols shows that alcohol inhibition of aniline hydroxylation is regulated by hydrophobicity and steric effects. No role for electronic factors can be discerned. Similarities are found between alcohol inhibition and the binding of alkyl amines to cytochrome P-450, suggesting that alcohols may bind to the amine binding site.

LUMO energies and hydrophobicity as determinants of mutagenicity by nitroaromatic compounds in Salmonella typhimurium.

Quantitative structure-activity relationships have been derived for the mutagenic activity of 47 nitroaromatic compounds acting on Salmonella typhimurium (TA100) and 66 acting on TA98. The mutagenicity is linearly dependent on the energy of the lowest occupied molecular orbital and bilinearly dependent on the hydrophobicity (octanol/water log P) of the mutagens. The mechanism of action is considered in the light of these findings.

Mutagenicity of dimethyl heteroaromatic triazenes in the Ames test: the role of hydrophobicity and electronic effects.

The mutagenicities of five heterocyclic 3,3-dimethyltriazenes have been evaluated in the Ames test. The octanol-water partition coefficients (P) for these triazenes have been measured, and their electron distributions and molecular orbital energies were calculated using the MNDO semiempirical molecular orbital method. Molecular structures of three triazenes have been determined using X-ray crystallography. The mutagenicities of these five triazenes, which range from nearly inactive to very highly mutagenic, are well predicted by quantitative structure-activity relationships that had been derived previously for the mutagenicity of aryltriazenes. The form of these equations indicates that more hydrophobic and more electron-rich triazenes are more active in the Ames test. This supports the hypothesis that the ease of initial triazene activation by cytochrome P-450 governs the mutagenicity of these compounds.