The metallothionein-III gene (MT-IIA) is a major member of the human MT gene family. Metallothioneins (MTs) are low-molecular-weight, cysteine-rich proteins that bind and detoxify heavy metals. At least two different MT-IIA polymorphisms have been identified in humans, one or both of which may affect susceptibility to metal toxicity. The purpose of this study was to investigate whether these different genotypes affect the inducibility of MT-IIA mRNA in human lymphocytes treated with zinc (Zn), the major known inducer of MT-IIA in vitro. Fresh lymphocytes obtained from 16 healthy volunteers, aged 23-38 yr, were genotyped for the MT-IIA gene and tested for expression. A 43.5-bp HindIII-Taql fragment of the MT-IIA promoter was used to probe for the two known polymorphisms (a 7.8-kb vs. a 5.3-kb fragmnent, and a 1.7-kb vs. a 1.6-kb fragment). The allele frequencies of the 16 subjects were 14%, for 5.3-kb allele and 19% for 1.6-kb allele. In Northern blotting experiments, MT-II mRNA levels were induced over a wide range of Zn concentrations during 2-h exposures; specifcally, levels increased by 9- to 115-fold with exposure to 100 microM ZnCl, and by 16- to 311-fold with exposure to 200 microM ZnCl2. However, no significant differences in MT-IIA inducibility were found between the 7.8/5.3-kb allele pair (n = 4) and the 7.8/7.8-kb allele pair (n = 12) or between the 1.7/1.6-kb allele pair (n = 5) and the 1.7/1.7-kb allele pair (n = 11). Thus. MT-IIA is strongly inducible by Zn in human lymphocytes, but individual variations exceed those that can be attributed to the known promoter-region polymorphisms.